Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents

ABSTRACT

The present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel β-aryl-α-oxysubstituted alkylcarboxylic acids of general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them

FIELD OF THE INVENTION

The present invention relates to novel antiobesity andhypocholesterolemic compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates and pharmaceutically acceptable compositions containing them.More particularly, the present invention relates to novelβ-aryl-α-oxysubstituted alkylcarboxylic acids of the general formula(I), their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates and pharmaceuticallyacceptable compositions containing them.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their analogs, their derivatives, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, pharmaceutically acceptable solvatesand pharmaceutical compositions containing them.

The present invention also relates to novel intermediates, processes fortheir preparation and their use in the preparation of compounds offormula (I).

The compounds of the present invention lower total cholesterol (TC),increase high density lipoprotein (HDL) and decrease low densitylipoprotein (LDL), which have a beneficial effect on coronary heartdisease and atherosclerosis.

The compounds of general formula (I) are useful in reducing body weightand for the treatment and/or prophylaxis of diseases such ashypertension, coronary heart disease, atherosclerosis, stroke,peripheral vascular diseases and related disorders. These compounds areuseful for the treatment of familial hypercholesterolemia,hypertriglyceridemia, lowering of atherogenic lipoproteins, VLDL (verylow density lipoprotein) and LDL. The compounds of the present inventioncan be used for the treatment of certain renal diseases includingglomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis and nephropathy. The compounds of general formula (I)are also useful for the treatment and/or prophylaxis of insulinresistance (type II diabetes), leptin resistance, impaired glucosetolerance, dyslipidemia, disorders related to syndrome X such ashypertension, obesity, insulin resistance, coronary heart disease andother cardiovascular disorders. These compounds may also be useful asaldose reductase inhibitors, for improving cognitive functions indementia, treating diabetic complications, disorders related toendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy,pancreatitis, arteriosclerosis, retinopathy, xanthoma, inflammation andfor the treatment of cancer. The compounds of the present invention areuseful in the treatment and/or prophylaxis of the above said diseases incombination/concomitant with one or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol and probucol.

BACKGROUND OF THE INVENTION

Atherosclerosis and other peripheral vascular diseases are the majorcauses effecting the quality of life of millions of people. Therefore,considerable attention has been directed towards understanding theetiology of hypercholesterolemia and hyperlipidemia and development ofeffective therapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), Intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations, (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al., (Br. Med. J., 282 (1981), 1741-1744) have shown thatincrease in HDL-particles may decrease the number of sites of stenosisin coronary arteries of human, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo el al,Arteriosclerosis 6 (1986) 434-441 have shown by in vitro experiment thatHDL is capable of removing cholesterol from cells. They suggest that HDLmay deplete tissues of excess free cholesterol and transfer it to liver(Macikinnon et al., J. Biol. chem. 261 (1986), 2548-2552). Therefore,agents that increase HDL cholesterol would have therapeutic significancefor the treatment of hypercholesterolemia and coronary heart diseases(CHD).

Obesity is a disease highly prevalent in affluent societies and in thedeveloping world and is a major cause of morbidity and mortality. It isa state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyeffects the quality of large population in the world. Insulin resistanceis the diminished ability of insulin to exert its biological actionacross a broad range of concentrations. In insulin resistance, the bodysecretes abnormally high amounts of insulin to compensate for thisdefect; failing which, the plasma glucose concentration inevitably risesand develops into diabetes. Among the developed countries, diabetesmellitus is a common problem and is associated with a variety ofabnormalities including obesity, hypertension, hyperlipidemia (J. Clin.Invest., 75 (1985) 809-817; N. Engl. J. Med 317 (1987) 350-357; J. Clin.Endocrinol. Metab., 66 (1988) 580-583; J. Clin. Invest. 68 (1975)957-969) and other renal complications (patent publication No. WO95/21608). It is now increasingly being recognized that insulinresistance and relative hyperinsulinemia have a contributory role inobesity, hypertension, atherosclerosis and type 2 diabetes mellitus. Theassociation of insulin resistance with obesity, hypertension and anginahas been described as a syndrome having insulin resistance as thecentral pathogenic link-Syndrome-X.

Hyperlipidemia is the primary cause for cardiovascular (CVD) and otherperipheral vascular diseases. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein)seen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help in preventing cardiovascular diseases.

Peroxisome proliferator activated receptors (PPAR) are members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, 135 (1994) 798-800) and energy homeostasis (Cell, 83(1995) 803-812), whereas the alpha (α) isoform of PPAR (PPARα) mediatesfatty acid oxidation (Trend Endocrin. Metab., 4 (1993) 291-296) therebyresulting in reduction of circulating free fatty acid in plasma (CurrentBiol. 5 (1995) 618-621). PPARα agonists have been found useful for thetreatment of obesity (WO 97/36579). It has been recently disclosed thatthere exists synergism for the molecules, which are agonists for bothPPARα and: PPARγ and suggested to be useful for the treatment ofsyndrome X (WO 97/25042). Similar synergism between the insulinsensitizer (PPARγ agonist) and HMG CoA reductase inhibitor has beenobserved which may be useful for the treatment of atherosclerosis andxanthoma (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, 79 (1994)1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated, less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., 94(1997) 237-241) and inhibition of expression of prostate cancer tissue(Cancer Research 58 (1998) 3344-3352). This would be useful in thetreatment of certain types of cancer, which express PPARγ and could leadto a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases and such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci. (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto the PPAR agonist expression and thereby lower plasma leptinconcentrations. However, it has been recently disclosed that compoundshaving insulin sensitizing property also possess leptin sensitizationactivity. They lower the circulating plasma leptin concentrations byimproving the target cell response to leptin (WO 98/02159).

A few β-aryl-α-hydroxy propionic acids, their derivatives and theiranalogs have been reported to be useful in the treatment ofhyperglycemia and hypercholesterolemia. Some of such compounds describedin the prior art are outlined below:

i) U.S. Pat. No. 5,306,726, WO 91/19702 disclose several3-aryl-2-hydroxypropionic acid derivatives of general formulas (IIa) and(IIb) as hypolipidemic and hypoglycemic agents.

Examples of these compounds are shown in formulas (II c) and (II d)

ii) International publication Nos. WO 95/03038 and WO 96/04260 disclosescompounds of formula (II e)

wherein R^(a) represents 2-benzoxazolyl or 2-pyridyl and R^(b) representCF₃, CH₂OCH₃ or CH₃. A typical example is(S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoicacid (II f).

iii) International publication Nos. WO 94/13650, WO 94/01420 and WO95/17394 disclose the compounds of general formula (II g)

wherein A¹ represents aromatic heterocycle, A² represents substitutedbenzene ring and A³ represents a moiety of formula (CH₂)_(m)—CH—(OR¹),wherein R¹ represents alkyl groups, m is an integer; X representssubstituted or unsubstituted N; Y represents C═O or C═S; R² representsOR³ where R³ may be alkyl, aralkyl, or aryl group; n represents aninteger in the range of 2-6.

An example of these compounds is shown in formula (IIh).

iii) U.S. Pat. No. 5,227,490 disclose compounds of general formula (IIi)

wherein R¹ is chosen independently from (C₁-C₆)alkyl, aryl(C₄-C₁₀)alkyl,aryl, carboxy, (C₁-C₆)alkyloxy, carboxy(C₀-C₆)alkyl,hydroxy(C₀-C₆)alkyl, (C₁-C₄)alkylsulfonyl(C₀-C₆)alkyl,(C₀-C₄)alkylamino(C₀-C₆)alkyl, aryl(C₀-C₁₀)alkylamino(C₀-C₆)alkyl,(C₂-C₁₀)acylamino(C₀-C₆)alkyl, (C₁-C₄)carboalkoxy(C₀-C₆)alkyl or halogenatom; R² is chosen from hydrogen, halogen, hydroxy, (C₁-C₆)alkyloxy,aryl(C₀-C₄)alkyl, aryl(C₀-C₆)alkyloxy, (C₁-C₆)alkyl wherein the alkylgroup is unsubstituted or substituted with one or more groups chosenfrom hydroxy, (C₁-C₄)alkyloxy, Amino(C₁-C₁₀)alkylcarbonyl,aryl(C₀-C₁₀)alkylcarbonyl, aryl(C₀-C₁₀)alkylcabonylamino,(C₁-C₆)alkylsulfonyl, aryl(C₀-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, aryl(C₀-C₁₀)alkylsulfonylamino,(C₁-C₁₀)alkyloxycarbonylamino, aryl(C₀-C₆)alkylamino,aryl(C₀-C₆)alkylcarbonylamino, amino, carboxy, aryl, carbonyl-P-or SO₂—Pwherein P is a single L or D amino acid or a sequence of 2-4 L or Damino acids connected by amide linkage; or R² represents carboxyl,(C₁-C₆)alkylcarbonyl, aryl(C₁-C₁₀)alkylcarbonyl,(C₁-C₆)alkyloxycarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,aryl(C₀-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,aryl(C₀-C₆)alkyloxycarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl oraryl(C₀-C₆)alkyloxycarbonyl and provided that when there is more thanone R² on the same carbon atom they may be the same or different; R³ ishydrogen, (C₁-C₆)alkyl, aryl(C₁-C₁₀)alkyl, Z is NR⁴R⁵ wherein R⁴ and R⁵are independently hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₁₀)alkyl wherein saidalkyl groups are unsubstituted or substituted with (C₁-C₄)alkyloxy,carboxy (C₀-C₆)alkyl, hydroxy, halogen or Z represents a 4-9 memberedmono or bicyclic ring system containing 1, 2 or 3 heteroatoms chosenfrom N, O or S and either unsubstituted or substituted with R⁴ or R⁵ br

Y is (C₁-C₁₀)alkyl either unsubstituted or unsubstituted with one ormore groups selected from R⁴ or R⁵; or Y represents (C₄-C₈)cycloalkyl,aryl, (C₀-C₃)alkylaryl(C₀-C₃)alkyl,(C₀-C₃)alkylaryl(C₀-C₃)alkylcarbonyl,(C₀-C₃)alkylaryl(C₀-C₃)alkylcarboxamido,(C₀-C₃)alkylaryloxy(C₀-C₃)alkyl, (C₀-C₃)alkyloxy(C₀-C₆)alkyl,

or —(CH₂)_(m)—Q—(CH)_(n) where Q is a C₂-C₈ membered heterocyclic ringcontaining 1, 2 or 3 heteroatoms chosen from N, O or S and substitutedor unsubstituted with oxo, thio, or (C₁-C₆)alkyl and m and n are chosenfrom the integers 0, 1, 2 or 3;X is O, S, SO, SO₂, CO, —NR⁴CO—, CONR⁴—, —CH₂—, —CH═CH—, —C═C—, —NR⁴CS—,—CSNR⁴— or SO₂NR⁴— or NR⁴SO₂;

An example of these compounds is shown in formula (II j)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for lowering cholesteroland reducing body weight with beneficial effects in the treatment and/orprophylaxis of diseases related to increased levels of lipids,atherosclerosis, coronary artery diseases, Syndrome-X, impaired glucosetolerance, insulin resistance, insulin resistance leading to type 2diabetes and diabetes complications thereof, for the treatment ofdiseases wherein insulin resistance is the pathophysiological mechanismand for the treatment of hypertension, with better efficacy, potency andlower toxicity, we focussed our research to develop new compoundseffective in the treatment of the above mentioned diseases. Effort inthis direction has led to compounds having general formula (I).

The main objective of the present invention is therefore, to providenovel β-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them, or their mixtures.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures which may have agonist activity against PPARα and/orPPARγ, and optionally inhibit HMG CoA reductase, in addition to havingagonist activity against PPARα and/or PPARγ.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures having enhanced activities, without toxic effect or withreduced toxic effect.

Yet another objective of the present invention is a process for thepreparation of novel β-aryl-α-oxysubstituted alkylcarboxylic acids offormula (I), their derivatives, their analogs, their tautomeric forms,their stereoisomers, their polymorphs, their pharmaceutically acceptablesalts and their pharmaceutically acceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their analogs, their derivatives, their tautomers, theirstereoisomers, their polymorphs, their salts, solvates or their mixturesin combination with suitable carriers, solvents, diluents and othermedia normally employed in preparing such compositions.

Another objective of the present invention is to provide novelintermediates, a process for their preparation and use of theintermediates in processes for preparation of β-aryl-α-oxysubstitutedalkyl carboxylic acids of formula (I), their derivatives, their analogs,their tautomers, their stereoisomers, their polymorphs, their salts andtheir pharmaceutically acceptable solvates.

DETAILED DESCRIPTION OF THE INVENTION

β-Aryl α-oxysubstituted propionic acids, their derivatives and theiranalogs of the present invention have the general formula (I)

wherein the groups R¹, R², R³, R⁴ and the groups R⁵ and R⁶ when attachedto carbon atom, may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; one or both of R⁵ andR⁶ may also represent an oxo group when they are attached to carbonatom; R⁵ and R⁶ when attached to nitrogen atom represent hydrogen,hydroxy, formyl or unsubstituted or substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio groups, carboxylic acidderivatives, or sulfonic acid derivatives; X represents a heteroatomselected from oxygen, sulfur or NR¹¹ where R¹¹ represents hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonylgroups; Ar represents an unsubstituted or substituted divalent single orfused aromatic or heterocyclic group; R⁷ represents hydrogen atom,hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substitutedaralkyl group or forms a bond together with the adjacent group R⁸; R⁸represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acylor unsubstituted or substituted aralkyl or R⁸ forms a bond together withR⁷; R⁹ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl groups; R¹⁰ representshydrogen or unsubstituted or substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkylgroups; Y represents oxygen or NR¹², where R¹² represents hydrogen,alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl orheteroaralkyl groups; R¹⁰ and R¹² together may form a 5 or 6 memberedcyclic structure containing carbon atoms, at least one nitrogen atom andwhich may optionally contain one or two additional heteroatoms selectedfrom oxygen, sulfur or nitrogen; the linking group represented by—(CH₂)_(n)—(O)_(m)— may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or1.

Suitable groups represented by R¹-R⁴ and the groups R⁵ and R⁶when-attached to carbon atom, may be selected from hydrogen, halogenatom such as fluorine, chlorine, bromine or iodine; hydroxy, cyano,nitro, formyl, substituted or unsubstituted (C₁-C₁₂)alkyl group,especially, linear or branched (C₁-C₁₀)alkyl group, such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl,iso-pentyl, hexyl, heptyl, octyl and the like; cyclo(C₃-C₆)alkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like,the cycloalkyl group may be substituted; (C₁-C₆)alkoxy such as methoxy,ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may besubstituted; cyclo(C₃-C₆)alkoxy group such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, thecycloalkoxy group may be substituted; aryl group such as phenyl,naphthyl and the like, the aryl group may be substituted; aryloxy groupsuch as phenoxy, naphthyloxy and the like, the aryloxy group may besubstituted; aralkyl such as benzyl, phenethyl, C₆H₅CH₂CH₂CH₂,naphthylmethyl and the like, the aralkyl group may be substituted andthe substituted aralkyl is a group such as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂,CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like; aralkoxy group such asbenzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and thelike, the aralkoxy group may be substituted; heterocyclyl groups such asaziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and thelike, the heterocyclyl group may be substituted; heteroaryl group suchas pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryl and the like, theheteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are asdefined earlier and may be substituted; acyl group such as acetyl,propionyl, benzoyl and the like, the acyl group may be substituted;acyloxy group such as OOCMe, OOCEt, OOCPh and the like, which may besubstituted; acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇,NHCOC₆H₅ and the like, which may be substituted; monoalkylamino groupsuch as NHCH₃, NHC₂H₅, NHC₃H₇, NHC₆H₁₃, and the like, which may besubstituted; dialkylamino group such as N(CH₃)₂, NCH₃(C₂H₅), N(C₂H₅)₂and the like, which may be substituted; arylamino group such as HNC₆H₅,NCH₃(C₆H₅), NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may besubstituted; aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH,C₆H₅CH₂NCH₃ and the like, which may be substituted; amino group;alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like,which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl,naphthyloxycarbonyl and the like, the aryloxycarbonyl group may besubstituted; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may besubstituted; (C₁-C₆)alkylthio which may be substituted;alkoxycarbonylamino group such as NHCOOC₂H₅, NHCOOCH₃ and the like,which may be substituted; aryloxycarbonylamino group such as NHCOOC₆H₅,NCH₃COOC₆H₅, NC₂H₅COOC₆H₅, NHCOOC₆H₄CH₃, NHCOOC₆HOCH₃ and the like,which may be substituted; aralkoxycarbonylamino group such asNHCOOCH₂C₆H₅, NHCOOCH₂CH₂C₆H₅, N(CH₃)COOCH₂C₆H₅, N(C₂H₅)COOCH₂C₆H₅,NHCOOCH₂C₆H₄—CH₃, NHCOOCH₂C₆H₄OCH₃ and the like, which may besubstituted, carboxylic acid or its derivatives such as amides, likeCONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh and the like, thecarboxylic acid derivatives may be substituted; sulfonic acid or itsderivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and the like, thesulfonic acid derivatives may be substituted. One or both of R⁵ and R⁶may also represent an oxo group, when they are attached to carbon atom.

When the groups represented by R¹-R⁴ and the groups R⁵ and R⁶ whenattached to carbon atom are substituted, the substituents may beselected from halogen, hydroxy, nitro, thio or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, aryloxy, aralkoxy, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl,alkylamino, alkylthio groups, carboxylic acid or its derivatives orsulfonic acid or its derivatives. These groups are as defined above.

It is preferred that the substituents on R¹-R⁶ represent halogen atomsuch as fluorine, chlorine or bromine; alkyl group such as methyl,ethyl, iso-propyl, n-propyl, n-butyl; cycloalkyl group such ascyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl;(C₁-C₃)alkoxy, benzyloxy, hydroxy group, acyl or acyloxy groups.

Suitable R⁵ and R⁶ when attached to nitrogen atom is selected fromhydrogen, hydroxy, formyl; substituted or unsubstituted (C₁-C₁₂)alkylgroup, especially, linear or branched (C₁-C₆)alkyl group, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl,n-pentyl, isopentyl, hexyl and the like; (C₁-C₆)alkoxy such as methoxy,ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may besubstituted, cyclo(C₃-C₆)alkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like, the cycloalkyl group may besubstituted; cyclo(C₃-C₆)alkoxy group such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, thecycloalkoxy group may be substituted; aryl group such as phenyl,naphthyl and the like, the aryl group may be substituted; aralkyl suchas benzyl, phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, thearalkyl group may be substituted and the substituted aralkyl is a groupsuch as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and thelike; aryloxy group such as phenoxy, naphthyloxy and the like, thearyloxy group may be substituted; aralkoxy group such as benzyloxy,phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, thearalkoxy group may be substituted; heterocyclyl groups such asaziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and thelike, the heterocyclyl group may be substituted; heteroaryl group suchas pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryl and the like, theheteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are asdefined earlier and may be substituted; acyl group such as acetyl,propionyl, benzoyl and the like, the acyl group may be substituted;acyloxy group such as OOCMe, OOCEt, OOCPh and the like, which may besubstituted; monoalkylamino group such as NHCH₃, NHC₂H₅, NHC₃H₇, NHC₆H₁₃and the like, which may be substituted; dialkylamino group such asN(CH₃)₂, NCH₃(C₂H₅), N(C₂H₅)₂ and the like, which may be substituted;acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇, NHCOC₆H₅ and thelike, which may be substituted; arylamino group such as HNC₆H₅,NCH₃(C₆H₅), NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may besubstituted; amino group; aralkylamino group such as C₆H₅CH₂NH,C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and the like, which may be substituted;alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl and thelike, which may be substituted; aryloxycarbonyl group such asphenoxycarbonyl, naphthyloxycarbonyl and the like, which may besubstituted; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may besubstituted; (C₁-C₆)alkylthio, which may be substituted; carboxylic acidderivatives such as amides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂,CONHph and the like, the carboxylic acid derivatives may be substituted;sulfonic acid derivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ andthe like, the sulfonic acid derivatives may be substituted.

When the groups represented by R⁵ and R⁶ attached to nitrogen aresubstituted, preferred substituents may be selected from halogen such asfluorine or chlorine; hydroxy, acyl, acyloxy or amino groups. Thesegroups are as defined above.

Suitable X includes oxygen, sulfur or a group NR¹¹, preferably oxygenand sulfur. Suitably R¹¹ represents hydrogen, (C₁-C₆)alkyl group such asmethyl, ethyl, propyl and the like; (C₃-C₆)cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; arylgroup such as phenyl, naphthyl and the like; aralkyl group such asbenzyl, phenethyl and the like; acyl group such as acetyl, propanoyl,butanoyl, benzoyl and the like; (C₁-C₆)alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl and the like; aryloxycarbonyl such asphenoxycarbonyl, CH₃OC₆H₄OCO, Hal-C₆H₄OCO, CH₃C₆H₄OCO,naphthyloxycarbonyl and the like; aralkoxycarbonyl such asbenzyloxycarbonyl, phenethyloxycarbonyl and the like; the groupsrepresented by R¹¹ may be substituted or unsubstituted. When the groupsrepresented by R¹¹ are substituted, the substituents may be selectedfrom halogen, optionally halogenated lower alkyl, hydroxy, andoptionally halogenated (C₁-C₃)alkoxy groups. These groups are as definedabove.

It is preferred that the group represented by Ar includes substituted orunsubstituted groups selected from divalent phenylene, naphthylene,pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl,dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl,pyrazolyl, benzothiazolyl, benzoxazolyl and the like. The substituentson the group represented by Ar may be selected from linear or branchedoptionally halogenated (C₁-C₆)alkyl, optionally halogenated(C₁-C₃)alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic orsulfonic acids and their derivatives. The substituents are defined asthey are for R¹-R⁴.

It is more preferred that Ar represent substituted or unsubstituteddivalent, phenylene, naphthylene, benzofuryl, indolyl, indolinyl,quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolylgroups.

It is still more preferred that Ar is represented by divalent phenylene,naphthylene or benzofuryl, which may be unsubstituted or substituted byalkyl, haloalkyl, methoxy or haloalkoxy groups.

Suitable R⁷ includes hydrogen, hydroxy, lower alkyl groups such asmethyl, ethyl or propyl; (C₁-C₃)alkoxy group such as methoxy, ethoxy,propoxy and the like; halogen atom such as fluorine, chlorine, bromineor iodine; aralkyl such as benzyl, phenethyl and the like, which may beunsubstituted or substituted or R⁷ together with R⁸ represents a bond.The substituents are selected from halogen, hydroxy or alkyl groups.

Suitable R⁸ may be hydrogen, hydroxy, lower alkyl groups such as methyl,ethyl or propyl; (C₁-C₃)alkoxy such as methoxy, ethoxy, propoxy and thelike; halogen atom such as fluorine, chlorine, bromine or iodine;(C₂-C₁₀)acyl group such as acetyl, propanoyl, butanoyl, pentanoyl,benzoyl and the like; aralkyl such as benzyl, phenethyl and the like,which may be unsubstituted or substituted or R⁸ together with R⁷ forms abond. The substituents are selected from halogen, hydroxy or alkylgroups.

Suitable groups represented by R⁹ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like, the alkyl group may be substituted;(C₃-C₇)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like, the cycloalkyl group may be substituted; arylgroup such as phenyl, naphthyl and the like, the aryl group may besubstituted; aralkyl group such as benzyl, phenethyl and the like,wherein the alkyl moiety may contain (C₁-C₆) atoms, wherein the arylmoiety may be substituted; heteroaryl group such as pyridyl, thienyl,pyrrolyl, furyl and the like, the heteroaryl group may be substituted;heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl,oxazolethyl and the like, the heteroaralkyl group may be substituted;heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and thelike, the heterocyclyl group may be substituted; linear or branched(C₂-C₁₆)acyl group such as acetyl, propanoyl, butanoyl, benzoyl,octanoyl, decanoyl and the like, which may be substituted;(C₁-C₆)alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl andthe like, the alkoxycarbonyl group may be substituted; aryloxycarbonylsuch as phenoxycarbonyl, naphthyloxycarbonyl and the like, the arylgroup may be substituted; (C₁-C₆)alkylaminocarbonyl, the alkyl group maybe substituted; arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyland the like, the aryl moiety may be substituted. The substituents maybe selected from halogen, hydroxy, nitro or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl,acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy,aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl,alkylthio, thioalkyl groups, carboxylic acid or its derivatives orsulfonic acid or its derivatives. The substituents are as defined above.

Suitable groups represented by R¹⁰ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like, the alkyl group may be substituted;(C₃-C₇)cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and thelike, the cycloalkyl group may be substituted; aryl group such asphenyl, naphthyl and the like, the aryl group may be substituted;heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like,the heteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkyl group such asbenzyl, phenethyl and the like, the aralkyl group may be substituted;heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and thelike, the heterocyclyl group may be substituted. The substituents on R¹⁰may be selected from halogen, hydroxy, nitro or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl,aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio,thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acidor its derivatives. The substituents are as defined above.

Suitable groups represented by R¹² may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like; hydroxy(C₁-C₆)alkyl; aryl group such as phenyl,naphthyl and the like; aralkyl group such as benzyl, phenethyl and thelike; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyland the like; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyland the like; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazolemethyl, oxazolethyl and the like.

Suitable ring structures formed by R¹⁰ and R¹² together may be selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.

Suitable m is an integer ranging from 0-1. It is preferred that whenm=0, Ar represents substituted or unsubstituted benzofuryl,benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, ordihydrobenzopyranyl group and when m=1, Ar represents substituted orunsubstituted groups selected from divalent phenylene, naphthylene,pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl,dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl,pyrazolyl, benzothiazolyl, benzoxazolyl and the like.

It is preferred that when m=0, Ar represents a divalent benzofurylgroup, more preferably benzofuran-2,5-diyl group and when m=1, Arrepresents a phenylene group. Suitable n is an integer ranging from 1 to4, preferably n represents an integer 1 or 2.

It is preferred that when m=1, n represents 2.

It is also preferred that when m=0, n represents 1.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, M, Fe, Cu, Zn,Mn; salts of organic bases such as N,N′-diacetylethylenediamine,betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine,piperidine, procaine, purines, theobromine, triethylamine,trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine,ethylenediamine, N,N′-diphenylethylenediamine,N,N′-dibenzylethylenediamine, N-benzyl phenylethylamine, choline,choline hydroxide, dicyclohexylamine, benzylamine, phenylethylamine,dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine,purine, spermidine, and the like; chiral bases like alkylphenylamine,glycinol, phenyl glycinol and the like, salts of natural amino acidssuch as glycine, alanine, valine, leucine, isoleucine, norleucine,tyrosine, cystine, cysteine, methionine, proline, hydroxy proline,histidine, ornithine, lysine, arginine, serine, threonine,phenylalanine; unnatural amino acids such as D-isomers or substitutedamino acids; guanidine, substituted guanidine wherein the substituentsare selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium orsubstituted ammonium salts and aluminum salts. Salts may include acidaddition salts where appropriate which are, sulphates, nitrates,phosphates, perchlorates, borates, hydrohalides, acetates, tartrates,maleates, citrates, succinates, palmoates, methanesulphonates,benzoates, salicylates, hydroxynaphthoates, benzenesulfonates,ascorbates, glycerophosphates, ketoglutarates and the like.Pharmaceutically acceptable solvates may be hydrates or comprising othersolvents of crystallization such as alcohols.

Particularly useful compounds according to the present inventioninclude:

-   Ethyl    (E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   Ethyl    (E)-3-[4-[2-2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   Ethyl    (Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   (±) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (+) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate,-   (−) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   Ethyl    (E/Z)-3-[2-2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate;-   Ethyl    (E)-3-[2-2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate;-   Ethyl    (Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate;-   Ethyl    (E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   Ethyl    (E)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   Ethyl    (Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate,-   (±) Methyl    3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;-   (+) Methyl    3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;-   (−)    Methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate,-   (±)    Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (+)    Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (−)    Methyl-3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (±) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy    propanoate;-   (+) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy    propanoate;-   (−) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy    propanoate;-   (±) Methyl    2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (+) Methyl    2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (−) Methyl    2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   Ethyl    (E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   Ethyl    (E)-3-[(4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   Ethyl    (Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;-   (±) Methyl    3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (+) Methyl    3-[4-[2-<3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   (−) Methyl    3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;-   Ethyl    (E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate;-   Ethyl    (E)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate;-   Ethyl    (Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate;-   (±) Methyl    3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate,-   (+) Methyl    3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;-   (−) Methyl    3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;-   (±) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;-   (+) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;-   (−) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;-   (±) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;-   (+) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;-   (−) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;-   (±) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate;-   (+) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate;-   (−) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate;-   (±) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate;-   (+) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate;-   (−) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate;-   (±) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate;-   (+) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate;-   (−) Ethyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate;-   Ethyl    (E/Z)-3-[4-[2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;-   Ethyl    (E)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;-   Ethyl    (Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;-   (±) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;-   (+) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;-   (−) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;-   Ethyl    (E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;-   Ethyl    (E)-3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;-   Ethyl    (Z)-3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;-   (±) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;-   (+) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;-   (−) Methyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;-   Ethyl    (E/Z)-3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propenoate;-   Ethyl    (E)-3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propenoate;-   Ethyl    (Z)-3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propenoate;-   (±) Methyl    3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;-   (+) Methyl    3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;-   (−) Methyl    3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propanoate;-   Ethyl    (E/Z)-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propenoate;-   Ethyl    (E)-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propenoate;-   Ethyl    (Z)-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propenoate;-   (±) Methyl    3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propanoate;-   (+) Methyl    3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propanoate;-   (−) Methyl    3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxy    propanoate;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide-   (±)    N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (+)    N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (−)    N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide,-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (±)    N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (+)    N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (−)    N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (±)    N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (+)    N-Benzyl-3-[4-[2-2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide,-   (−)    N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (±)    N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (+)    N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (−)    N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;-   (±)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[4-[2-3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic,    acid and its salts;-   (±)    3-[4-[2-(2-(3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic    acid and its salts;-   (−)    3-[4-[2-2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic    acid and its salts;-   (+)    3-[4-[2-2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (±)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (+)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (−)    3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (±) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy    propanoate;-   (+) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy    propanoate;-   (−) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxy    propanoate;-   (±)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (+)    2-Methyl-3′-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (−)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (±) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy    propanoate;-   (+) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy    propanoate;-   (−) Methyl    2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxy    propanoate;-   (±)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (+)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (−)    2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic    acid and its salts;-   (±) 4-Nitrophenyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy    propanoate;-   (+) 4-Nitrophenyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy    propanoate;-   (−) 4-Nitrophenyl    3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy    propanoate;-   (±)    3-[4-(4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic    acid and its salts;-   (+)    3-[4-(4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic    acid and its salts;-   (−)    3-[4-(4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic    acid and its salts;-   (±)    4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;-   (+)    4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;    and-   (−)    4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate.

According to a feature of the present invention, the compound of generalformula (I) where R⁷ and R⁵ together represent a bond, Y representsoxygen atom, R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, X, n, m and Ar are asdefined earlier, can be prepared by any of the following routes shown inScheme I.

Route (1): The reaction of a compound of the general formula (IIIa)where all symbols are as defined earlier with a compound of formula(IIIb) where R⁹, R¹⁰ are as defined earlier excluding hydrogen and R¹⁴represents (C₁-C₆)alkyl, to yield compound of general formula (I) whereR⁷, R⁵ together represent a bond and Y represents an oxygen atom may becarried out neat in the presence of a base such as alkali metal hydrideslike NaH or KH; organolithiums like CH₃Li, BuLi and the like; alkoxidessuch as NaOMe, NaOEt, K⁺BuO⁻ and the like or mixtures thereof. Thereaction may be carried out in the presence of solvents such as THF,dioxane, DMF, DMSO, DME and the like or mixtures thereof. HMPA may beused as cosolvent. The reaction temperature may range from −78° C. to50° C., preferably at a temperature in the range of −10° C. to 30° C.The reaction is more effective under anhydrous conditions. The compoundof general formula (IIIb) may be prepared according to the proceduredescribed in the literature (Annalen. Chemie, (1996) 53, 699).

Alternatively the compound of formula (I) may be prepared by reactingthe compound of formula (IIIa) where all symbols are as defined earlierwith Wittig reagents such as Hal⁻PPh₃ ⁻CH—(OR⁹)CO₂R¹⁰, where R⁹ and R¹⁰are as defined earlier under similar reaction conditions as describedabove.

Route (2): The reaction of a compound of general formula (Mc) where allsymbols are as defined earlier with a compound of general formula (IIId)where R⁷, R⁹ together represent a bond, L¹ is a leaving group such ashalogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like, preferably a halogen atom andall other symbols are as defined earlier to produce a compound ofgeneral formula (I) defined above may be carried out in the presence ofsolvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or amixture thereof. The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar or He. Thereaction may be effected in the presence of a base such as alkalis likesodium hydroxide or potassium hydroxide, alkali metal carbonates likesodium carbonate or potassium carbonate; alkali metal hydrides such assodium hydride or potassium hydride; organometallic bases like n-butyllithium; alkali metal amides like sodamide or mixtures thereof. Theamount of base may range from 1 to 5 equivalents, based on the amount ofthe compound of formula (IIIc), preferably the amount of base rangesfrom 1 to 3 equivalents. Phase transfer catalysts such astetraalkylammonium halide or hydroxide may be added. The reaction may becarried out at a temperature in the range of 0° C. to 150° C.,preferably at a temperature in the range of 15° C. to 100° C. Theduration of the reaction may range from 0.25 to 48 hours, preferablyfrom 0.25 to 12 hours.

Route (3): The reaction of a compound of formula (IIIe) where allsymbols are as defined earlier with a compound of formula (IIIf) whereR⁹=R¹⁰ and are as defined earlier excluding hydrogen, to produce acompound of the formula (I) where R⁷ and R⁸ together represent a bondand all other symbols are as defined earlier may be carried out neat inthe presence of a base such as alkali metal hydrides like NaH or KH;organolithiums like CH₃Li, BuLi and the like; alkoxides such as NaOMe,NaOEt, K⁺BuO⁻ and the like or mixtures thereof. The reaction may becarried out in the presence of aprotic solvents such as THF, dioxane,DMF, DMSO, DME and the like or mixtures thereof HMPA may be used ascosolvent. The reaction temperature may range from −78° C. to 100° C.,preferably at a temperature in the range of −10° C. to 50° C.

Route (4): The reaction of a compound of the general formula (IIIa)where all symbols are as defined earlier, with a compound of formula(IIIg) where R⁸ represents hydrogen atom, R⁹ and R¹⁰ are as definedearlier may be carried out in the presence of a base. The nature of thebase is not critical. Any base normally employed for aldol condensationreaction may be employed; bases like metal hydride such as NaH or KH,metal alkoxides such as NaOMe, K⁺ BuO⁻ or NaOEt and the like; metalamides such as LiNH₂ or LiN(iPr)₂ may be used. Aprotic solvent such asTHF, ether, or dioxane may be used. The reaction may be carried out inan inert atmosphere which may be maintained by using inert gases such asN₂, Ar, or He and the reaction is more effective under anhydrousconditions. Temperature in the range of −80° C. to 35° C. may be used.The β-hydroxy product initially produced may be dehydrated underconventional dehydration conditions such as treating with p-TSA insolvents such as benzene or toluene. The nature of solvent anddehydrating agent is not critical. Temperature in the range of 20° C. toreflux temperature of the solvent used may be employed, preferably atreflux temperature of the solvent by continuous removal of water using aDean Stark water separator.

Route (5): The reaction of compound of formula (IIIh) where all symbolsare as defined earlier and L¹ represents a leaving group such as halogenatom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonateand the like with a compound of formula (IIIi) where R⁷ and R⁸ togetherrepresent a bond and R⁹, R¹⁰ and Ar are as defined earlier to produce acompound of the formula (I) where m=1 and all other symbols are asdefined above may be carried out in the presence of aprotic solventssuch as THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar or He. The reaction maybe effected in the presence of a base such as K₂CO₃, Na₂CO₃ or NaH ormixtures thereof. Acetone may be used as solvent when Na₂CO₃ or K₂CO₃ isused as a base. The reaction temperature may range from 0° C.-120° C.,preferably at a temperature in the range of 30° C.-100° C. The durationof the reaction may range from 1 to 24 hours, preferably from 2 to 12hours. The compound of formula (IIIi) can be prepared according to knownprocedures by a Wittig Horner reaction between the hydroxy protectedaryl aldehyde such as benzyloxyaryl aldehyde and compound of formula(IIIb), followed by deprotection.

Route (6): The reaction of compound of general formula (IIIj) where allsymbols are as defined earlier with a compound of general formula (IIIi)where R⁷ and R⁵ together represent a bond and R⁹, R¹⁰ and Ar are asdefined earlier to produce a compound of the formula (I) where m=1 andall other symbols are as defined above may be carried out using suitablecoupling agents such as dicyclohexyl urea,triaryl-phosphine/dialkylazadicarboxylate such as PPh₃/DEAD and thelike. The reaction may be carried out in the presence of solvents suchas THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, CCl₄ and the like.The inert atmosphere may be maintained by using inert gases such as N₂,Ar or He. The reaction may be effected in the presence of DMAP, HOBT andthey may be used in the range of 0.05 to 2 equivalents, preferably 0.25to 1 equivalents. The reaction temperature may be in the range of 0° C.to 100° C., preferably at a temperature in the range of 20° C. to 80° C.The duration of the reaction may range from 0.5 to 24 hours, preferablyfrom 6 to 12 hours.

In another embodiment of the present invention, the compound of thegeneral formula (I) where R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, X n, m, andAr are as defined earlier, R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, unsubstituted or substituted aralkyl group, R⁸represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acylor unsubstituted or substituted aralkyl and Y represents oxygen can beprepared by one or more of the processes shown in Scheme-II:

Route 7: The reduction of compound of the formula (IVa) which representsa compound of formula (I) where R⁷ and R⁸ together represent a bond andY represents an oxygen atom and all other symbols are as definedearlier, obtained as described earlier (Scheme-I), to yield a compoundof the general formula (I) where R⁷ and R⁸ each represent a hydrogenatom and all symbols are as defined earlier, may be carried out in thepresence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C,and the like. Mixtures of catalysts may be used. The reaction may alsobe conducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed. High pressures may be used to reduce the time.The catalyst may be preferably 5-10% Pd/C and the amount of catalystused may range from 1-50% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium in alcohol or sodiumamalgam in alcohol preferably methanol. The hydrogenation may be carriedout in the presence of metal catalysts containing chiral ligands toobtain a compound of formula (I) in optically active form. The metalcatalyst may contain rhodium, ruthenium, indium and the like. The chiralligands may preferably be chiral phosphines such as(2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane,1,2-bis(2-methoxyphenylphenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butaneand the like. Any suitable chiral catalyst may be employed which wouldgive required optical purity of the product (I) (Ref: Principles ofAsymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp 311-316, Ed.Baldwin J. E.).

Route 8: The reaction of compound of formula (IVb) where R¹⁰ is asdefined earlier excluding hydrogen, L² is a leaving group such ashalogen atom and all other symbols are as defined earlier with analcohol of general formula (IVc), where R⁹ is as defined earlierexcluding hydrogen to produce a compound of the formula (I) definedearlier may be carried out in the presence of solvents such as THF, DMF,DMSO, DME and the like or mixtures thereof. The reaction may be carriedout in an inert atmosphere which may be maintained by using inert gasessuch as N₂, Ar or He. The reaction may be effected in the presence of abase such as KOH, NaOH, NaOMe, NaOEt, K⁺BuO⁻ or NaH or mixtures thereof.Phase transfer catalysts such as tetraalkylammonium halides orhydroxides may be employed. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-100° C.The duration of the reaction may range from 1 to 12 hours, preferablyfrom 2 to 6 hours. The compound of general formula (IVb) and itspreparation has been disclosed in our International publication No. WO98/52946.

Route 9: The reaction of compound of formula (IIIh) defined earlier withcompound of formula (IIIi) where all symbols are as defined earlier toproduce a compound of the formula (I) where m=1 and all other symbolsare as defined above, may be carried out in the presence of solventssuch as THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere which is maintainedby using inert gases such as N₂, Ar or He. The reaction may be effectedin the presence of a base such as K₂CO₃, Na₂CO₃, NaH and the like ormixtures thereof. Acetone may be used as a solvent when K₂CO₃ or Na₂CO₃is used as a base. The reaction temperature may range from 20° C.-120°C., preferably at a temperature in the range of 30° C.-80° C. Theduration of the reaction may range from: 1 to 24 hours, preferably from2 to 12 hours. The compound of formula (IIIi) may be prepared by WittigHorner reaction between the protected hydroxyaryl aldehyde and compoundof formula (IIIb) followed by reduction of the double bond anddeprotection. Alternatively, the compound of formula (IIIi) may beprepared by following a procedure disclosed in WO 94/01420.

Route 10: The reaction of compound of general formula (mj) definedearlier with a compound of general formula (IIIi) where all symbols areas defined earlier to produce a compound of the formula (I) where m=1and all other symbols are as defined above may be carried out usingsuitable coupling agents such as dicyclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD and the like.The reaction may be carried out in the presence of solvents such as THF,DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbon tetrachloride and thelike. The reaction may be carried out in an inert atmosphere which maybe maintained by using inert gases such as N₂, Ar or He. The reactionmay be effected in the presence of DMAP, HOBT and they may be used inthe range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents.The reaction temperature may be in the range of 0° C. to 100° C.,preferably at a temperature in the range of 20° C. to 80° C. Theduration of the reaction may range from 0.5 to 24 hours, preferably from6 to 12 hours.

Route 11: The reaction of compound of formula (IVd) which represents acompound of formula (I) where R⁹ represents hydrogen atom and all othersymbols are as defined earlier with a compound of formula (IVe) where R⁹is as defined earlier excluding hydrogen and L² is a leaving group suchas a halogen atom, may be carried out in the presence of solvents suchas TH, DMF, DMSO, DME and the like. The reaction may carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The reaction may be effected in the presence of a basesuch as KOH, NaOH, NaOMe, K⁺BuO⁻, NaH and the like. Phase transfercatalyst such as tetraalkylammonium halides or hydroxides may beemployed. The reaction temperature may range from 20° C. to 150° C.,preferably at a temperature in the range of 30° C. to 100° C. Theduration of the reaction may range from 1 to 24 hours, preferably from 2to 6 hours.

Route 12: The reaction of a compound of the general formula (IIIa) asdefined above with a compound of formula (IIIg) where R⁸ is hydrogen,R⁹, and R¹⁰ are as defined earlier may be carried out under conventionalconditions. The base is not critical. Any base normally employed foraldol condensation reaction may be employed, metal hydride such as NaHor KH; metal alkoxides such as NaOMe, K^(t)BuO⁻ or NaOEt; metal amidessuch as LiNH₂, or LiN(iPr)₂. Aprotic solvent such as THF may be used.Inert atmosphere may be employed such as argon and the reaction is moreeffective under anhydrous conditions. Temperature in the range of −80°C. to 25° C. may be used. The β-hydroxy aldol product may bedehydroxylated using conventional methods, conveniently by ionichydrogenation technique such as by treating with a trialkyl silane inthe presence of an acid such as trifluoroacetic acid. Solvent such asCH₂Cl₂ may be used. Favorably, the reaction proceeds at 25° C. A highertemperature may be employed if the reaction is slow.

Route 13: The reaction of a compound of general formula (IIIc) where allsymbols are as defined earlier with a compound of general formula (IIId)where L¹ is a leaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethane-sulfonate and the like, preferably L¹is a halogen atom, and all other symbols are as defined earlier toproduce a compound of general formula (I) may be carried out in thepresence of solvents such as DMSO, DMF, DME. THF, dioxane, ether and thelike or mixtures thereof. The reaction may be carried out in an inertatmosphere which may be maintained by using inert gases such as N₂, Aror He. The reaction may be effected in the presence of a base such asalkalis like sodium hydroxide, potassium hydroxide and the like; alkalimetal carbonates like sodium carbonate, potassium carbonate and thelike; alkali metal hydrides such as sodium hydride or potassium hydride;organometallic bases like n-butyl lithium; alkali metal amides likesodamide or mixtures thereof. The amount of base may range from 1 to 5equivalents, based on the amount of the compound of formula (IIIc),preferably the amount of base ranges from 1 to 3 equivalents. Thereaction may be carried out at a temperature in the range of 0° C. to150° C., preferably at a temperature in the range of 15° C. to 100° C.The duration of the reaction may range from 0.25 to 24 hours, preferablyfrom 0.25 to 12 hours.

Route 14: The conversion of compound of formula (IVf) where all symbolsare as defined earlier to a compound of formula (I) where all symbolsare as defined earlier may be carried out either in the presence of baseor acid and the selection of base or acid is not critical. Any basenormally used for hydrolysis of nitrile to acid may be employed, such asmetal hydroxides such as NaOH or KOH in an aqueous solvent or any acidnormally used for hydrolysis of nitrile to ester may be employed such asdry HCl in excess of alcohol such as methanol, ethanol, propanol and thelike. The reaction may be carried out at a temperature in the range of0° C. to reflux temperature of the solvent used, preferably at atemperature in the range of 25° C. to reflux temperature of the solventused. The duration of the reaction may range from 0.25 to 48 hrs.

Route 15: The reaction of a compound of formula (IVg) where R¹⁰ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier with a compound of formula (IVc) where R⁹ is as defined earlierexcluding hydrogen to produce a compound of formula (I) (by a rhodiumcarbenoid mediated insertion reaction) may be carried out in thepresence of rhodium (II) salts such as rhodium (II) acetate. Thereaction may be carried out in the presence of solvents such as benzene,toluene, dioxane, ether, THF and the like or mixtures thereof or whenpracticable in the presence of R⁹OH as solvent at any temperatureproviding a convenient rate of formation of the required product,generally at an elevated temperature, such as reflux temperature of thesolvent. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar or He. The duration of the reaction may range from 0.5 to24 h, preferably from 0.5 to 6 h.

The compound of formula (I) where R¹⁰ represents hydrogen atom may beprepared by hydrolysing, using conventional methods, a compound offormula (I) where R¹⁰ represents all groups defined earlier excludinghydrogen. The hydrolysis may be carried out in the presence of a basesuch as Na₂CO₃ and a suitable solvent such as methanol, ethanol and thelike or mixtures thereof. The reaction may be carried out at atemperature in the range of 20° C.-40° C., preferably at 25° C.-30° C.The reaction time may range from 2 to 12 h, preferably from 4 to 8 h.

The compound of general formula (I) where Y represents oxygen and R¹⁰represents hydrogen or lower alkyl group may be converted to compound offormula (I), where Y represents NR¹² by reaction with appropriate aminesof the formula NHR¹⁰R¹², where R¹⁰ and R¹² are as defined earlier toyield a compound of formula (I) where Y represents NR¹² and all othersymbols are as defined earlier. Alternatively, the compound of formula(I) where YR¹⁰ represents OH may be converted to acid halide, preferablyYR¹⁰=Cl, by reacting with appropriate reagents such as oxalyl chloride,thionyl chloride and the like, followed by treatment with amines of theformula NHR¹⁰R¹² where R¹¹ and R¹² are as defined earlier.Alternatively, mixed anhydrides may be prepared from compound of formula(I) where YR¹⁰ represents OH and all other symbols are as definedearlier by treating with acid halides such acetyl chloride, acetylbromide, pivaloyl chloride, dichlorobenzoyl chloride and the like. Thereaction may be carried out in the presence of suitable base such aspyridine, triethylamine, diisopropyl ethylamine and the like. Solventssuch as halogenated hydrocarbons like CHCl₃ or CH₂Cl₂; hydrocarbons suchas benzene, toluene, xylene and the like may be used. The reaction maybe carried out at a temperature in the range of 40° C. to 40° C.,preferably at a temperature in the range of 0° C. to 20° C. The acidhalide or mixed anhydride thus prepared may further be treated withappropriate amines of the formula NHR¹⁰R¹² where R¹⁰ and R¹² are asdefined earlier to yield a compound of formula (I) where Y representsNR¹² and all other symbols are as defined earlier.

The process for the preparation of compounds of formula (IIIa) have beendescribed in our International publication No. WO 98/52946.

In another embodiment of the present invention the novel intermediate offormula (IVf)

wherein the groups R¹, R², R³, R⁴ and the groups R⁵ and R⁶ when attachedto carbon atom, may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; one or both of R⁵ andR⁶ may also represent an oxo group when they are attached to carbonatom; R⁵ and R⁶ when attached to nitrogen atom represent hydrogen,hydroxy, formyl or unsubstituted or substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio groups, carboxylic acidderivatives, or sulfonic acid derivatives; X represents a heteroatomselected from oxygen, sulfur or NR¹¹ where R¹¹ represents hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonylgroups; Ar represents an unsubstituted or substituted divalent single orfused aromatic or heterocyclic group; R⁷ represents hydrogen atom,hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substitutedaralkyl group or forms a bond together with the adjacent group R⁸; R⁸represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acylor unsubstituted or substituted aralkyl or R⁸ forms a bond together withR⁷; R⁹ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl or heteroaralkyl groups; the linking grouprepresented by —(CH₂)_(n)—(O)_(m)— may be attached either throughnitrogen atom or carbon atom; n is an integer ranging from 1-4 and m isan integer 0 or 1 and a process for its preparation and its use in thepreparation of β-aryl-α-oxysubstituted alkylcarboxylic acids isprovided.

The compound of formula (IVf) where R⁷ and R⁸ each represent hydrogenatoms and all other symbols are as defined earlier is prepared by aprocess outlined in Scheme-III.

The reaction of a compound of formula (IIIa) where all symbols are asdefined earlier with a compound of formula (IVh) where R⁹ is as definedearlier excluding hydrogen and Hal represents a halogen atom such as Cl,Br or I to produce a compound of formula (IVi) may be carried out underconventional conditions in the presence of a base. The base is notcritical. Any base normally employed for Wittig reaction may beemployed, metal hydride such as NaH or KH; metal alkoxides such asNaOMe, K^(t)BuO⁻, or NaOEt or metal amides such as LiNH₂ or LiN(iPr)₂.Aprotic solvent such as THF, DMSO, dioxane, DME and the like may beused. Mixture of solvents may be used. HMPA may be used as a cosolvent.Inert atmosphere may be employed which may be maintained by using inertgases such as argon and the reaction is more effective under anhydrousconditions. Temperature in the range of −80° C. to 100° C. may be used.

The compound of (IVi) where all symbols are as defined earlier and R⁹ isas defined earlier excluding hydrogen may be converted to a compound offormula (IVj) where R⁷ and R⁹ represent hydrogen atoms and all othersymbols are as defined earlier, by treating with an alcohol of formulaR⁹OH where R⁹ is as defined earlier excluding hydrogen under anhydrousconditions in the presence of a strong anhydrous acid such asp-toluenesulfonic acid.

The compound of formula (IVj) defined above upon treatment withtrialkylsilyl cyanide such as trimethylsilyl cyanide produces a compoundof formula (IVf) where R⁷ and R⁸ represent hydrogen atoms, R⁹ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier.

In still another embodiment of the present invention the novelintermediate of formula (IVg)

wherein the groups R¹, R², R³, R⁴ and the groups R⁵ and R⁶ when attachedto carbon atom, may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl,aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; one or both of R⁵ andR⁶ may also represent an oxo group when they are attached to carbonatom; R⁵ and R⁶ when attached to nitrogen atom represent hydrogen,hydroxy, formyl or unsubstituted or substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino,monoalkylamino, dialkylamino, arylamino, aralkylamino, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylthio groups, carboxylic acidderivatives, or sulfonic acid derivatives; X represents a heteroatomselected from oxygen, sulfur or NR¹¹ where R¹¹ represents hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonylgroups; Ar represents an unsubstituted or substituted divalent single orfused aromatic or heterocyclic group; R⁷ represents hydrogen atom,hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substitutedaralkyl group; R¹⁰ represents hydrogen or unsubstituted or substitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl or heteroaralkyl groups; the linking group represented by—(CH₂)_(n)—(O)_(m)— may be attached either through nitrogen atom orcarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or 1and a process for its preparation and its use in the preparation ofβ-aryl-α-oxysubstituted alkylcarboxylic acids is provided.

The compound of formula (IVg) where all other symbols are as definedearlier may be prepared by reacting a compound of formula (IVk)

where R⁵ is a hydrogen atom and all symbols are as defined earlier, withan appropriate diazotizing agent.

The diazotization reaction may be carried out under conventionalconditions. A suitable diazotizing agent is an alkyl nitrile, such asiso-amyl nitrile. The reaction may be carried out in presence ofsolvents such as THF, dioxane, ether, benzene and the like or a mixturethereof. Temperature in the range of −50° C. to 80° C. may be used. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar or He. The duration ofthe reaction may range from 1 to 24 h, preferably, 1 to 12 h.

The compound of formula (IVk) may also be prepared by a reaction between(IIIh) where all symbols are as defined earlier and a compound offormula (IVl)

where R⁵ is a hydrogen atom and all other symbols are as definedearlier.

The reaction of compound of formula (IIIh) where all symbols are asdefined earlier and a compound of formula (IVl) where all symbols are asdefined earlier may be carried out in the presence of solvents such asTHF, DMF, DMSO, DME and the like or mixtures thereof. The reaction maybe carried out in an inert atmosphere which is maintained by using inertgases such as N₂, Ar or He. The reaction may be effected in the presenceof a base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof. Acetone maybe used as a solvent when K₂CO₃ or Na₂CO₃ is used as a base. Thereaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours.

As used in this application the term neat means the reaction is carriedout without the use of solvent.

It is appreciated that in any of the above mentioned reactions, anyreactive group in the substrate molecule may be protected according toconventional chemical practice. Suitable protecting groups in any of theabove mentioned reactions are those used conventionally in the art. Themethods of formation and removal of such protecting groups are thoseconventional methods appropriate to the molecule being protected.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium hydroxide,potassium t-butoxide, calcium hydroxide, magnesium hydroxide and thelike, in solvents like ether, THF, methanol, t-butanol, dioxane,isopropanol, ethanol etc. Mixtures of solvents may be used. Organicbases like lysine, arginine, diethanolamine, choline, guanidine andtheir derivatives etc. may also be used. Alternatively, acid additionsalts wherever applicable are prepared by treatment with acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, aceticacid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid,ascorbic acid, palmitic acid, succinic acid, benzoic acid,benzenesulfonic acid, tartaric acid and the like in solvents like ethylacetate, ether, alcohols, acetone, THF, dioxane etc. Mixtures ofsolvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR¹⁰represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, aminoacids, aminoalcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide; the diastereomers may be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

Various polymorphs of a compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formulaI) under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe NMR spectroscopy, IR spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The present invention provides a pharmaceutical composition, containingthe compounds of the general formula (I) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharmaceutically acceptable salts or theirpharmaceutically acceptable solvates in combination with the usualpharmaceutically employed carriers, diluents and the like, useful forthe treatment and/or prophylaxis of diseases such as hypertension,coronary heart disease, atherosclerosis, stroke, peripheral vasculardiseases and related disorders. These compounds are useful for thetreatment of familial hypercholesterolemia, hypertriglyceridemia,lowering of atherogenic lipoproteins, VLDL and LDL. The compounds of thepresent invention can be used for the treatment of certain renaldiseases including glomerulonephritis, glomerulosclerosis, nephroticsyndrome, hypertensive nephrosclerosis, nephropathy. The compounds ofgeneral formula (I) are also useful for the treatment/prophylaxis ofinsulin resistance (type II diabetes), leptin resistance, impairedglucose tolerance, dyslipidemia, disorders related to syndrome X such ashypertension, obesity, insulin resistance, coronary heart disease, andother cardiovascular disorders. These compounds may also be useful asaldose reductase inhibitors, for improving cognitive functions indementia, as inflammatory agents, treating diabetic complications,disorders related to endothelial cell activation, psoriasis, polycysticovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis,myotonic dystrophy, pancreatitis, retinopathy, arteriosclerosis,xanthoma and for the treatment of cancer. The compounds of the presentinvention are useful in the treatment and/or prophylaxis of the abovesaid diseases in combination/concomitant; with one or more HMG CoAreductase inhibitors, hypolipidemic/hypolipoproteinemic agents such asfibric acid derivatives, nicotinic acid, cholestyramine, colestipol,probucol or their combination. The compounds of the present invention incombination with HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents can be administered together orwithin such a period to act synergistically. The HMG CoA reductaseinhibitors may be selected from those used for the treatment orprevention of hyperlipidemia such as lovastatin, provastatin,simvastatin, fluvastatin, atorvastatin, cerivastatin and their analogsthereof. Suitable fibric acid derivative may be gemfibrozil, clofibrate,fenofibrate, ciprofibrate, benzafibrate and their analogs thereof.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I) as defined above,their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptable saltsor their pharmaceutically acceptable solvates and one or more HMG CoAreductase inhibitors, hypolipidemic/hypolipoproteinemic agents such asfibric acid derivatives, nicotinic acid, cholestyramine, colestipol,probucol in combination with the usual pharmaceutically employedcarriers, diluents and the like.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavorants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%, preferably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active ingredientwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the polymorphic form can becombined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavourants, sweeteners, excipients and the like. Forparenteral administration, the polymorphic form can be combined withsterile aqueous or organic media to form injectable solutions orsuspensions. For example, solutions in sesame or peanut oil, aqueouspropylene glycol and the like can be used, as well as aqueous solutionsof water-soluble pharmaceutically-acceptable acid addition salts orsalts with base of the compounds. Aqueous solutions with the activeingredient dissolved in polyhydroxylated castor oil may also be used forinjectable solutions. The injectable solutions prepared in this mannercan then be administered intravenously, intraperitoneally,subcutaneously, or intramuscularly, with intramuscular administrationbeing preferred in humans.

For nasal administration, the preparation may contain the polymorphicforms of the present invention dissolved or suspended in a liquidcarrier, in particular an aqueous carrier, for aerosol application. Thecarrier may contain additives such as solubilizing agents, such aspropylene glycol, surfactants, absorption enhancers such as lecithin(phosphatidylcholine) or cyclodextrin or preservatives such asparabenes.

Tablets, dragees or capsules having talc and/or a carbohydrate carriedbinder or the like are particularly suitable for any oral application.Preferably, carriers for tablets, dragees or capsules include lactose,corn starch and/or potato starch. A syrup or elixir can be used in caseswhere a sweetened vehicle can be employed.

A typical tablet production method is exemplified below:

Tablet Production Example:

a) 1) Active ingredient 30 g 2) Lactose 95 g 3) Corn starch 30 g 4)Carboxymethyl cellulose 44 g 5) Magnesium stearate 1 g 200 g for 1000tablets

The ingredients 1 to 3 are uniformly blended with water and granulatedafter drying under reduced pressure. The ingredient 4 and 5 are mixedwell with the granules and compressed by a tabletting machine to prepare1000 tablets each containing 30 mg of active ingredient.

b) 1) Active ingredient 30 g 2) Calcium phosphate 90 g 3) Lactose 40 g4) Corn starch 35 g 5) Polyvinyl pyrrolidone 3.5 g 6) Magnesium stearate1.5 g 200 g for 1000 tablets

The ingredients 1-4 are uniformly moistened with an aqueous solution of5 and granulated after drying under reduced pressure. Ingredient 6 isadded and granules are compressed by a tabletting machine to prepare1000 tablets containing 30 mg of ingredient 1.

The compound of the formula (I) as defined above are clinicallyadministered to mammals, including man, via either oral, nasal,pulmonary, transdermal or parenteral, rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmicsolution or an ointment. Administration by the oral route is preferred,being more convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the patient cannot swallowthe medication, or absorption following oral administration is impaired,as by disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 100 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg 1 kg body weight per dayadministered singly or as a divided dose. However, the optimum dosagefor the individual subject being treated will be determined by theperson responsible for treatment, generally smaller doses beingadministered initially and thereafter increments made to determine themost suitable dosage.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

Preparation 1 (±) 4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde

A mixture of 2H-1,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol),4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassiumcarbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) wasstirred at 80° C. for 10 h. Water (100 mL) was added and extracted withethyl acetate (2×75 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried (Na₂SO₄), filtered and the solventwas evaporated. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet ether (2:8) to afford the titlecompound (2.9 g, 91%) as a colorless solid. mp: 75-78° C.

¹H NMR (CDCl₃, 200 MHz): δ 4.37 (s, 4H), 4.62 (s, 2H), 6.96-7.26(complex, 6H), 7.82 (d, J=8.40 Hz, 2H), 9.89 (s, 1H).

Preparation 2 (±)6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene

A mixture of 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethyl methanesulfonate(0.49 g, 1.82 mmol), 2-hydroxy-6-cyanonaphthalene (0.28 g, 1.65 mmol)and potassium carbonate (1.15 g, 8.28 mmol) in dry dimethyl formamide(15 mL) was stirred at 80° C. for 12 h. Water (50 mL) was added andextracted with ethyl acetate (2×25 mL). The combined ethyl acetatelayers were washed with water (25 mL), brine (20 mL), dried (Na₂SO₄),filtered and the solvent was evaporated under reduced pressure. Theresidue was chromatographed over silica gel using a mixture of ethylacetate and pet. ether to afford the title compound (0.41 g, 72%) as apale yellow solid. mp: 94-96° C.

¹H NMR (CDCl₃, 200 MHz): δ 3.05 (t, J=5.21 Hz, 2H), 3.79-3.85 (complex,4H), 4.31 (t, J=5.82 Hz, 2H), 6.64-6.78 (complex, 2H), 6.97-7.25(complex, 4H), 7.53-7.80 (complex, 3H), 8.13 (s, 1H).

Preparation 3 (±)6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthaldehyde

To a solution of (±)6-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene (8 g,22.9 mmol) obtained in preparation 2 in dry tetrahydrofuran (15 mL) wasadded diisobutyl aluminum hydride (93 mL, 20% in toluene) at −70° C.over a period of 1 h. After complete addition, the reaction mixture wasstirred at 25° C. for 16 h. At the end of this time, ethyl formate (20mL) was added and stirred for 1 h at 25° C. Saturated ammonium chloridesolution (15 mL) was added. The reaction mixture was acidified with 10%sulphuric acid and extracted with ethyl acetate (2×75 mL). The combinedethyl acetate layers were washed with water (2×50 mL), brine (50 mL),dried (Na₂SO₄), filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (10:90) to afford the titlecompound (4.5 g, 56%) as a pale yellow solid. mp: 100-102° C.

¹H NMR (CDCl₃, 200 MHz): δ 3.06 (t, J=5.20 Hz, 2H), 3.72-3.86 (complex,4H), 4.33 (t, J=5.67 Hz, 2H), 6.60-6.79 (complex, 2H), 6.97-7.25(complex, 4H), 7.74-7.93 (complex, 3H), 8.25 (s, 1H), 10.09 (s, 1H).

Preparation 4(±)4-[4-Methyl-3,4-dihydro-1,4-benzoxazin-2-yl]methoxybenzaldehyde

To a solution of 4-methyl-3,4-dihydro-1,4-benzoxazin-2-methanol (6.0 g,33.51 mmol) in dichloromethane (20 mL) was added triethylamine (10.15 g,100.5 mmol) under nitrogen atmosphere at 25° C. Methanesulfonyl chloride(5.75 g, 50.25 mmol) was added to the above reaction mixture at 0° C.and stirred for 10 h at 25° C. Water (50 mL) was added and extractedwith chloroform (2×25 mL). The combined organic extracts were washedwith water (50 mL), dried (Na₂SO₄), filtered and the solvent wasevaporated under reduced pressure. The residue was chromatographed oversilica gel using a mixture of ethyl acetate and hexane (2:8) to yield(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl methanesulfonate(3.7 g, 43%) as a syrup.

¹H NMR (CDCl₃, 200 MHz): δ 2.88 (s, 3H), 3.07 (s, 3H), 3.13-3.31(complex, 2H), 4.41 (d, J=5.20 Hz, 2H), 4.53-4.55 (complex, 1H),6.81-6.89 (complex, 4H). A mixture of(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methyl methanesulfonate (3.7g, 14.39 mmol), 4-hydroxy benzaldehyde (2.6 g, 21.29 mmol) and potassiumcarbonate (5.9 g, 42.7 mmol) in dry dimethyl formamide (30 mL) wasstirred at 80° C. for 10 h. Water (100 mL) was added and extracted withethyl acetate (2×70 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL) and dried (Na₂SO₄), filtered and thesolvent was evaporated under reduced pressure. The residue waschromatographed over silica gel using a mixture of ethyl acetate andpet. ether (2:8) to afford the title compound (1.3 g, 32%) as a thickliquid.

¹H NMR (CDCl₃, 200 MHz): 2.93 (s, 3H), 3.24-3.46 (complex, 2H),4.14-4.37 (complex, 2H), 4.68-4.71 (complex, 1H), 6.72-7.10 (complex,6H), 7.86 (d, J=8.80 Hz, 2H), 9.92 (s, 1H).

Preparation 5 (±)4-[4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-yl]methoxybenzaldehyde

The title compound (3.2 g, 80%) was prepared as a pale yellow solid from4-benzyl-3,4-dihydro-1,4-benzoxazin-2-methanol (4.0 g, 15.68 mmol) by aprocedure similar to that described for preparation 4. mp: 92-94° C.

¹H NMR (CDCl₃, 200 MHz): δ 3.38-3.43 (complex, 2H), 4.14-4.32 (complex,2H), 4.46 (d, J=7.80 Hz, 2H), 4.60-4.65 (complex, 1H), 6.65-6.89(complex, 4H), 7.00 (d, J=8.80 Hz, 2H), 7.32 (s, 5H), 7.83 (d, J=8.80Hz, 2H), 9.90 (s, 1H).

EXAMPLE 1 Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate

A solution of triethyl 2-ethoxyphosphonoacetate (W. Greli and H.Machleidt, Annalen Chemie, 1960, 699, 53). (7.8 g, 29.1 mmol) in drytetrahydrofuran (15 mL) was added slowly to a stirred, ice-cooledsuspension of sodium hydride (60% dispersion in oil) (1.39 g, 29.1 mmol)in dry tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture wasstirred at 0° C. for 30 minutes followed by the addition of a solutionof 4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (7.5 g,26.5 mmol) which is prepared according to the process described inPreparation 1 disclosed in our International publication No. WO98/52946, in dry tetrahydrofuran (20 mL). The mixture was allowed towarm to 25° C. and stirred further for 20 h. The solvent was evaporatedand the residue was suspended in water (100 mL) and extracted with ethylacetate (2×75 mL). The combined ethyl acetate layers were washed withwater (75 mL), brine (50 mL), dried (Na₂SO₄), filtered and the solventwas evaporated under reduced pressure. The residue was chromatographedover silica gel using a mixture of ethyl acetate and petroleum ether(2:8) as eluent to afford the title compound (8.0 g, 75%) as a gum(65:35 Z:E mixture of geometric isomers) (R. A. Aitken and G. L. Thom,Synthesis, 1989, 958).

¹H NMR (CDCl₃, 200 MHz) δ: 1.18 and 1.36 (combined 6H, isomeric OEt,triplet signals), 3.51 (t, J=4.48 Hz, 2H), 3.71 (t, J=5.39 Hz, 2H),3.89-4.03 (complex, 2H), 4.10-4.34 (complex, 6H), 6.07 (s, 0.35H, Eolefinic proton), 6.63-7.14 (complex, 6.65H), 7.73 (d, J=8.72 Hz, 2H).

EXAMPLE 2 (±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

A mixture of ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate(8.0 g, 20.0 mmol) obtained in example 1 and magnesium turnings (9.64 g,396.7 mmol) in dry methanol (50 mL) was stirred at 25° C. for 20 h. Atthe end of this time, water (50 mL) was added and pH was adjusted to ca7.0 using 10% aqueous hydrochloric acid and the solution was extractedwith ethyl acetate (2×10 mL). The combined organic extracts were washedwith water (75 mL), brine (75 mL), dried (Na₂SO₄), filtered and thesolvent was removed under reduced pressure. The residue waschromatographed over silica gel using a mixture of ethyl acetate andpet. ether (2:8) as an eluent to afford the title compound (5.0 g, 64%)as a gummy liquid.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=7.00 Hz, 3H), 2.93 (d, J=6.64 Hz,2H), 3.23-3.38 (complex, 1H), 3.43-3.72 (complex, 8H), 3.97 (t, J=6.90Hz, 1H), 4.14 (t, J=5.81 Hz, 2H), 4.19 (t, J=4.20 Hz, 2H), 6.55-6.83(complex, 6H), 7.13 (d, J=8.39 Hz, 2H).

EXAMPLE 3 Ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate

The title compound (0.8 g, 58%) was prepared as a gummy material from5-formyl-2-(2,3-dihydro-1,4-benzoxazin-4-yl)methyl benzofuran (1.0 g,3.41 mmol) by a procedure analogous to that described in example 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.06 and 1.38 (6H, OCH₂CH₃ and OCH₂CH₃,triplet signals), 3.48 (t, J=4.98 Hz, 2H), 3.89-4.18 (complex, 2H),4.28-4.40 (complex, 4H), 4.54 and 4.56 (combined, 2H, —NCH₂-signals),6.20 (0.5H E isomer of olefinic proton), 6.52 and 6.59 (combined, 1H),6.65-6.83 (complex, 2.5H), 7.08-7.11 (complex, 1H), 7.32-7.44 (complex,2H), 7.69 (d, J=8.30 Hz, 1H), 7.99 (s, 1H).

EXAMPLE 4 Ethyl(E/Z-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate

The title compound was prepared as a 38:62 ratio of geometric isomers(as measured by ¹H NMR) (3.2 g, 71%) as a gummy material, from4-[2-(2,3-dihydro-1,4 benzothiazin-4-yl)ethoxy]benzaldehyde (3.3 g,11.03 mmol) prepared according to the process described in preparation 2disclosed in our International publication No. WO 98/52946 by a methodanalogous to that described in example 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.14 and 1.35 (combined, 6H, isomeric—OCH₂CH₃ triplet signals), 3.02 (t, J=4.90 Hz, 2H), 3.69-3.88 (complex,4H), 3.92-4.03 (complex, 2H), 4.12-4.33 (complex, 4H), 6.06 (s, 0.38H, Eolefinic proton), 6.61-7.14 (complex, 6.62H), 7.73 (d, J=8.81 Hz, 2H).

EXAMPLE 5 (±) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate

The title compound (0.6 g, 78%) was prepared as a gum from ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate(0.8 g, 1.96 mmol) obtained in example 3 by a procedure analogous tothat described for example 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.5 (t, J=7.00 Hz, 3H), 3.07 (d, J=5.80 Hz2H), 3.28-3.67 (complex, 4H), 3.70 (s, 3H), 4.03 (t, J=6.00 Hz, 1H),4.28 (t, J=4.47 Hz, 2H), 4.54 (s, 2H), 6.52 (s, 1H), 6.62-6.89 (complex,4H), 7.10 (d, J=7.05 Hz, 1H), 7.35 (complex, 2H).

EXAMPLE 6 (±)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

The title compound (2.3 g, 76%) was prepared as a gummy liquid fromethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate(3.1 g, 7.50 mmol) obtained in example 4 by an analogous procedure tothat described in example 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=7.01 Hz, 3H), 2.93 (d, J=6.65 Hz,2H), 3.03 (t, J=5.21 Hz, 2H), 3.23-3.41 (complex, 1H), 3.52-3.80(complex, 8H), 3.97 (t, J=7.01 Hz, 1H), 4.14 (t, J=5.81 Hz, 2H),6.61-6.82 (complex, 4H), 6.92-7.05 (complex, 2H), 7.13 (d, J=8.53 Hz,2H).

EXAMPLE 7 (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

To a solution of (±) methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.6 g, 1.5 mmol) obtained in example 2 in dry tetrahydrofuran (5 mL)was added lithium diisopropyl amide (5.25 μL, 0.5 mL solution inTHF/hexane) at −78° C. After stirring for 1 h at −78° C., methyl iodide(0.75 mL) was added and the reaction mixture was allowed to warm to roomtemperature (ca 25° C.) and stirred for further 20 h at the sametemperature. Water (20 mL) was added, acidified with 1 N hydrochloricacid and extracted with ethyl acetate (2×25 mL). The combined ethylacetate layer was washed with water (25 mL), brine (25 mL), dried(Na₂SO₄), filtered and the solvent was evaporated under reduced pressureto afford the title compound (0.5 g, 80%) as an oil.

¹H NMR (CDCl₃, 200 MHz): δ1.21 (t, J=6.97 Hz, 3H), 1.31 (s, 3H), 2.95(s, 2H), 3.32-3.58 (complex, 4H), 3.62-3.84 (complex, 5H), 4.14 (t,J=5.81 Hz, 2H), 4.22 (t, J=4.25 Hz, 2H), 6.55-6.88 (complex, 6H), 7.08(d, J=8.63 Hz, 2H).

EXAMPLE 8 (±) Methyl2-2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

The title compound (0.6 g, 78%) was prepared as a brown liquid from (±)methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.6 g, 1.5 mmol) obtained in example 2 by an analogous procedure tothat described in example 7.

¹H NMR (CDCl₃, 200 MHz): δ 1.22 (t, J=6.96 Hz, 3H), 3.03-3.18 (complex,4H), 3.51 (t, J=4.20 Hz, 2H), 3.59-3.71 (complex, 7H), 4.14 (t, J=5.81Hz, 2H), 4.22 (t, J=4.24 Hz, 2H), 6.42-6.85 (complex, 6H), 6.90-7.32(complex 6H).

EXAMPLE 9 Ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate

The title compound (3.9 g, 97%) was obtained in 32:68 ratio of E:Zisomers as a white solid from4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (2.9 g, 9.7 mmol)obtained in preparation 1 by an analogous procedure to that described inexample 1. mp: 92-95° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.13-1.43 (complex, 6H), 3.88-4.02 (complex,2H), 4.07-4.40 (complex, 6H), 4.60 (s, 2H), 6.05 (s, 0.32H, E olefinicproton), 6.76-7.32 (complex, 6.68H), 7.71 (d, J=8.72 Hz, 2H).

EXAMPLE 10 (±) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

The title compound (1.0 g, 51%) was prepared as a colorless syrup fromethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate(2.0 g, 4.8 mmol) obtained in example 9 by a procedure analogous to thatdescribed in example 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.14 (t, J=7.00 Hz, 3H), 2.92 (d, J=6.60 Hz,2H), 3.25-3.41 (complex, 1H), 3.53-3.61 (complex, 1H), 3.68 (s, 3H),3.96 (t, J=7.00 Hz, 1H), 4.21-4.32 (complex, 4H), 4.68 (s, 2H), 6.77 (d,J=8.63 Hz, 2H), 6.98-7.33 (complex, 6H).

EXAMPLE 11 Ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxyl]naphthyl]-2-ethoxypropenoate

The title compound as a 1:1 mixture of E/Z isomers (1.74 g, 87%) wasprepared as a brown syrup from6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthaldehyde (1.5 g,4.29 mmol) obtained in preparation 3 by a procedure analogous to thatdescribed in example 1.

¹H NMR (CDCl₃, 200 MHz): δ 0.99-1.47 (complex, 6H), 3.06 (t, J=4.98 Hz,2H), 3.79-3.95 (complex, 4H), 3.99-4.18 (complex, 2H), 4.25-4.37(complex, 4H), 6.23 (s, 0.5H, E olefinic proton), 6.59-6.79 (complex,2H), 6.97-7.29 (complex, 4.5H), 7.57-7.95 (complex, 3H), 8.14 (s, 1H).

EXAMPLE 12 (±) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate

The title compound (1.25 g, 75%) was prepared as a colorless syrup fromethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate(1.7 g, 3.67 mmol) obtained in example 11 by an analogous procedure tothat described in example 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.14 (t, J=7.06 Hz, 3H), 3.06 (t, J=5.21 Hz,2H), 3.13 (d, J=7.15 Hz, 2H), 3.29-3.37 (complex, 1H), 3.57-3.64(complex, 1H), 3.70 (s, 3H), 3.77-3.83 (complex, 4H), 4.09 (t, J=7.20Hz, 1H), 4.25 (t, J=5.81 Hz, 2H), 6.62-6.79 (complex, 2H), 6.96-7.36(complex, 5H), 7.60-7.70 (complex, 3H).

EXAMPLE 13 (±) Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate

The title compound (0.14 g, 32%) was prepared as a gummy liquid from2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.36 g, 1.42mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol) usingconditions analogous to that described in preparation 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.24 (t, J=7.15 Hz, 3H), 2.71 (d, J=6.23 Hz,1H, D₂O exchangeable), 2.84-3.10 (complex, 2H), 3.50 (t, J=4.47 Hz, 2H),3.67 (t, J=5.48 Hz, 2H), 4.11-4.26 (complex, 6H), 4.37-4.39 (complex,1H), 6.61-6.86 (complex, 6H), 7.11 (d, J=8.62 Hz, 2H).

EXAMPLE 14 (±) Ethyl3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate

The title compound (1.9 g, 17%) was prepared as a gummy liquid from2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethyl methanesulfonate (8.2 g, 30.0mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 μg, 30.0 mmol) usingconditions analogous to that described in preparation 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.29 (t, J=7.11 Hz, 3H), 2.70-2.80 (bs, 1H,D₂O exchangeable), 2.82-3.15 (complex, 4H), 3.65-3.82 (complex, 4H),4.10-4.30 (complex, 4H), 4.28-4.40 (complex, 1H), 6.62-6.89 (complex,4H), 6.92-7.18 (complex, 4H).

EXAMPLE 15 (±) Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate

A solution of (±) ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate(0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5mL) was added to a stirred ice cooled suspension of sodium hydride (60%dispersion in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL)under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69mmol). The mixture was allowed to warm to 25° C. and stirring wascontinued for further 18 h. Water (25 mL) was added and extracted withethyl acetate (2×50 mL). The combined organic layer was washed withwater (50 mL), brine (50 mL), dried (Na₂SO₄) and filtered. The solventwas evaporated under reduced pressure and the residue waschromatographed over silica gel using a mixture of ethyl acetate andpet. ether (2:8) as eluent to afford the title compound (0.3 g) alongwith benzyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate.This mixture (1:1) is used in example 47 without any separation.

¹H NMR (CDCl₃, 200 MHz): δ 1.23 (t, J=7.05 Hz, 1.55H), 2.99 (d, J=7.06Hz, 4H), 3.00-3.72 (complex, 8H), 4.05-4.30 (complex, 12H), 4.32-4.71(complex, 4H), 5.13 (s, 2H), 6.55-6.89 (complex, 12H), 7.05-7.36(complex, 19H).

EXAMPLE 16 (±) Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate

The title compound (0.4 g, 52%) was prepared as a gummy liquid from2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g, 1.78mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol) usingconditions analogous to that described in preparation 2.

¹H NMR (CDCl₃, 200 MHz): δ0.84 (t, J=7.53 Hz, 3H), 1.19-1.34 (complex,5H), 1.43-1.55 (complex, 2H), 2.92 (d, J=6.32 Hz, 2H), 3.22-3.36(complex, 1H), 3.48-3.59 (complex, 3H), 3.68 (t, J=5.82 Hz, 2H), 3.93(t, J=6.20 Hz, 1H), 4.11-4.24 (complex, 6H), 6.61-6.86 (complex, 6H),7.13 (d, J=8.30 Hz, 2H).

EXAMPLE 17 (±) Ethyl3-[4-[2-2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate

The title compound (0.31 g, 50%) was prepared as a colorless syrup from2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.35 g, 1.3mmol), potassium carbonate (0.75 g, 5.4 mmol) and ethyl2-hexyloxy-3-(4-hydroxyphenyl)propanoate (0.4 g, 1.3 mmol) usingconditions analogous to that described in preparation 2.

¹H NMR (CDCl₃, 200 MHz): δ 0.85 (t, J=5.72 Hz, 3H), 1.20-1.34 (complex,7H), 1.40-1.66 (complex, 4H); 2.93 (d, J=6.00 Hz, 2H), 3.21-3.31(complex, 1H), 3.49-3.60 (complex, 3H), 3.68 (t, J=5.72 Hz, 2H), 3.93(t, J=5.81 Hz, 1H), 4.11-4.24 (complex, 6H), 6.62-6.81 (complex, 5H),7.09-7.16 (complex, 3H).

EXAMPLE 18 Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate

The title compound (0.92 g, 58%) was prepared as a mixture of E:Zisomers (40:60) as a syrupy liquid from4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (1.0 g, 3.0mmol) and triethyl 2-phenoxyphosphonoacetate (A. G. Schultz, et. al. J.Org. Chem., 1983, 48, 3408) (1.3 g, 4.0 mmol) by an analogous procedureto that described in example 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.06 and 1.18 (combined 3H, isomeric OCH₂CH₃,triplet signals), 3.43-3.57 (complex, 2H), 3.64-3.75 (complex, 2H),4.06-4.28 (complex, 6H), 6.60-6.90 (complex, 8H), 6.94-7.12 (complex,2H), 7.22-7.45 (complex, 3H), 7.64 (d, J=8.72 Hz, 1H).

EXAMPLE 19 (±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate

The title compound (0.49 g, 57%) was prepared as a gummy material fromethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate(0.9 g, 2.0 mmol) obtained in example 18 by an analogous procedure tothat described for example 2.

¹HNMR (CDCl₃, 200 MHz): δ 3.17 (d, J=6.20 Hz, 2H), 3.50 (t, J=4.30 Hz,2H), 3.65-3.70 (complex, 5H), 4.14 (t, J=5.76 Hz, 2H), 4.21 (t, J=4.15Hz, 2H), 4.75 (t, J=6.40 Hz, 1H), 6.61-6.98 (complex, 9H), 7.17-7.27(complex, 4H).

EXAMPLE 20 Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate

The title compound (3.7 g, 60%) was prepared as a mixture of E:Z isomers(35:65) as a gummy material from4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]benzaldehyde (4.0 g, 13.0mmol) and triethyl 2-phenoxyphosphonoacetate (A. G. Schultz, et. al. J.Org. Chem. 1983, 48, 3408), (5.07 g, 16.0 mmol) by an analogousprocedure to that described in example 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.05-1.36 (complex, 3H), 3.00-3.11 (complex,2H), 3.64-3.85 (complex, 4H), 4.09-4.30 (complex, 4H), 6.58-7.13(complex, 8H), 7.20-7.46 (complex, 4H), 7.65 (d, J=8.70 Hz, 2H).

EXAMPLE 21 (±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate

The title compound (2.3 g, 64%) was prepared as a gummy material fromethyl(E/Z-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate(3.7 g, 8.0 mmol) obtained in example 20 by an analogous procedure tothat described for example 2.

¹H NMR (CDCl₃, 200 MHz): δ 2.99 (t, J=5.43 Hz, 2H), 3.15 (d, J=5.99 Hz,2H), 3.60-3.78 (complex, 7H), 4.13 (t, J=5.40 Hz, 2H), 4.74 (t, J=6.23Hz, 1H), 6.58-6.89 (complex, 6H), 6.90-7.06 (complex, 2H), 7.11-7.30(complex, 5H).

EXAMPLE 22 Ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate

The title compound (0.4 g, 25%) was prepared as a mixture of E:Z isomers(1:1) as a brown liquid from4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxybenzaldehyde (1.2 g,4.24 mmol) obtained in preparation 4 by an analogous procedure to thatdescribed in example 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.36 (t, J=7.10 Hz, 6H), 2.90 (s, 3H),3.26-3.45 (complex, 2H), 3.99 (q, J=7.20 Hz, 2H), 4.10-4.38 (complex,4H), 4.50-4.60 (complex, 1H), 6.70 (d, J=7.47 Hz, 2H), 6.81-6.90(complex, 5H), 7.75 (d. J=8.80 Hz, 2H).

EXAMPLE 23 (±) Methyl3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate

The title compound (0.25 g, 65%) was prepared as a thick liquid fromethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate(0.4 g, 1.0 mmol) obtained in example 22 by an analogous procedure tothat described in example 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=7.00 Hz, 3H), 2.89 (s, 3H), 2.95(d, J=6.20 Hz, 2H), 3.19-3.41 (complex, 3H), 3.55-3.66 (complex, 1H),3.70 (s, 3H), 3.95-4.24 (complex, 3H), 4.60-4.64 (complex, 1H),6.64-7.08 (complex, 6H), 7.15 (d, J=8.40 Hz, 2H).

EXAMPLE 24 Ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate

The title compound (3.0 g, 76%) was prepared as E:Z isomers (1:1), as asyrupy liquid from4-[4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxybenzaldehyde (3.0 g,8.35 mmol) obtained in preparation 5 by a procedure analogous to thatdescribed for example 1.

¹H NMR (CDCl₃, 200 MHz): δ 1.33-1.40 (complex, 6H), 3.39-3.44 (complex,2H), 3.99 (q, J=7.00 Hz, 2H), 4.11-4.38 (complex, 4H), 4.46 (d, J=5.00Hz, 2H), 4.52-4.66 (complex, 1H), 6.60-6.97 (complex, 7H), 7.28 (s, 5H),7.75 (d, J=8.80 Hz, 2H).

EXAMPLE 25 (±) Methyl3-[4(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate

The title compound (1.5 g, 100%) was prepared from ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate(1.5 g, 3.17 mmol) obtained in example 24 by an analogous procedure tothat described in example 2.

¹H NMR (CDCl₃, 200 MHz): δ 1.17 (t, J=7.00 Hz, 3H), 2.96 (d, J=6.60 Hz2H), 3.31-3.57 (complex, 3H), 3.60-3.70 (complex, 1H), 3.71 (s, 3H),3.97-4.26 (complex, 3H), 4.47 (d, J=4.00 Hz, 2H), 4.56-4.61 (complex,1H), 6.68-6.90 (complex, 6H), 7.15 (d, J=8.50 Hz, 2H), 7.29 (s, 5H).

EXAMPLE 26 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid

To a solution of (±) methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (4.7 g, 12.2 mmol) obtained in example 2 in methanol (50 mL)was added aqueous 10% sodium hydroxide (28 mL). The mixture was stirredat 25° C. for 3 h. The solvent was removed under reduced pressure andthe residue was acidified with 2N hydrochloric acid and extracted withethyl acetate (2×100 mL). The combined ethyl acetate layers were washedwith water (75 mL), brine (50 mL), dried (Na₂SO₄), filtered and thesolvent was evaporated under reduced pressure. The residue waschromatographed over silica gel using ethyl acetate to afford the titlecompound (3.0 g, 66%) as a syrupy liquid.

¹H NMR (CDCl₃, 200 MHz): δ 1.17 (t, J=6.96 Hz, 3H), 2.85-3.12 (complex,2H), 3.40-3.61 (complex, 4H), 3.69 (t, J=5.72 Hz, 2H), 4.04 (dd, J=7.38and 4.27 Hz, 1H), 4.10-4.28 (complex, 4H), 6.52-6.85 (complex, 6H), 7.14(d, J=8.60 Hz, 2H), COOH proton is too broad to observe.

EXAMPLE 27 (±)3-[4-[2-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt

A mixture of (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.15 g, 0.4 mmol) obtained in example 26 and sodium methoxide(23.4 mg) in methanol (5 mL) was stirred at 25° C. for 2 h. The solventwas removed and the residue was triturated with dry ether (3×10 mL). Theprecipitated solid was filtered, washed with dry ether (2×5 mL) anddried over P₂O₅ under vacuum to afford the title compound (0.12 g, 75%)as a colorless hygroscopic solid.

¹H NMR (DMSO-d₆, 200 MHz): δ 0.98 (t, J=6.83 Hz, 3H), 2.60-2.69(complex, 1H), 2.78-2.92 (complex, 1H), 3.05-3.21 (complex, 2H),3.41-3.75 (complex, 5H), 4.08-4.21 (complex, 4H), 6.49-6.85 (complex,6H), 7.12 (d, J=8.30 Hz, 2H).

EXAMPLE 28 (±)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid

The title compound (0.5 g, 87%) was prepared as a gummy material from(±) methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate(0.6 g, 1.51 mmol) obtained in example 5 by a procedure analogous tothat described for example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.26 (t, J=7.06 Hz, 3H), 3.05-3.28 (complex,2H), 3.40-3.68 (complex, 4H), 4.09 (dd, J=7.47 and 4.24 Hz, 1H), 4.28(t, J=4.15 Hz, 2H), 4.53 (s, 2H), 6.52 (s, 1H), 6.60-6.90 (complex, 4H),7.13 (d, J=8.70 Hz, 1H), 7.32-7.36 (complex, 2H), COOH proton is toobroad to observe.

EXAMPLE 29 (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid

The title compound (1.4 g, 63%) was prepared as a gummy material from(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(2.3 g, 5.73 mmol) obtained in example 6 by a procedure analogous tothat described for example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.18 (t, J=7.00 Hz, 3H), 2.82-3.15 (complex,4H), 3.40-3.68 (complex, 2H), 3.70-3.81 (complex, 4H), 4.05 (dd, J=7.29and 4.33 Hz 1H), 4.16 (t, J=5.72 Hz, 2H), 6.68-6.74 (complex, 2H), 6.81(d, J=8.50 Hz, 2H), 6.94-7.06 (complex, 2H), 7.14 (d, J=8.50 Hz, 2H),COOH proton is too broad to observe.

EXAMPLE 30 (±)3-[4-[2(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt

The title compound (0.42 g, 81%) was prepared as a colorless solid from(±)3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.5 g, 1.30 mmol) obtained in example 29 by an analogous procedureto that described for example 27.

¹H NMR (CDCl₃, 200 MHz): δ 0.98 (t, J=7.00 Hz, 3H), 2.72-3.25 (complex,5H), 3.30-3.51 (complex, 1H), 3.61-3.73 (complex, 4H), 3.82-3.91(complex, 1H), 4.04 (t. J=5.72 Hz, 2H), 6.52-6.19 (complex, 4H),6.91-7.03 (complex, 2H), 7.10 (d. J=8.40 Hz, 2H).

EXAMPLE 31 (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide

A solution of oxalyl chloride (0.28 mL, 3.1 mmol) and (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.6 g, 1.55 mmol) obtained in example 29 in dry dichloromethane(10 mL) was refluxed for 2 h. The solvent and excess oxalyl chloridewere removed under reduced pressure. The residue was dissolved indichloromethane and stirred with aqueous ammonia (5 mL) for 30 min. Thereaction mixture was extracted with chloroform (2×25 mL). The combinedchloroform layers were washed with water (25 mL), dried (Na₂SO₄),filtered, and the solvent was evaporated under reduced pressure. Theresidue was chromatographed over silica gel using a mixture of ethylacetate and pet. ether (7:3) as an eluent to afford the title compound(0.32 g, 54%) as a white solid. mp: 120-122° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=6.96 Hz, 3H), 2.81-3.20 (complex,4H), 3.38-3.58 (complex, 2H), 3.71-3.90 (complex, 4H), 3.91 (dd, J=7.38and 3.73 Hz, 1H), 4.16 (t, J=5.58 Hz, 2H), 5.54 (bs, D₂O exchangeable,1H), 6.44 (bs, D₂O exchangeable, 1H), 6.59-6.84 (complex, 4H), 6.92-7.19(complex, 4H).

EXAMPLE 32 (±)N-Methyl-3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide

To an ice cooled solution of (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.78 mmol) obtained in example 29 and triethylamine (0.162g, 1.6 mmol) in dry chloromethane (10 mL) was added pivaloyl chloride(0.10 g, 0.86 mmol) and stirred for 30 min at 0° C. To the abovereaction mixture, methylamine (40% solution) (0.124 mL) was added at 25°C. and stirring was continued for 1 h at 25° C. Water (20 mL) was addedand extracted with ethyl acetate (2×20 mL). The combined organicextracts were washed with water (10 mL), brine (10 mL), dried (Na₂SO₄),filtered and the solvent was evaporated under reduced pressure. Theresidue was chromatographed over silica gel using a mixture of ethylacetate and pet. ether (1:1) to afford the title compound as a colorlesssolid. mp: 80-82° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.11 (t, J=7.00 Hz, 3H), 2.76 (d, J=4.89 Hz,3H), 2.81-2.88 (complex, 1H), 3.01-3.12 (complex, 3H), 3.39-3.52(complex, 2H), 3.70-3.81 (complex, 4H), 3.86-3.91 (complex, 1H), 4.14(t, J=5.81 Hz, 2H), 6.48 (bs, 1H), 6.61-6.81 (complex, 4H), 6.94-7.14(complex, 4H).

EXAMPLE 33 (±)3-[4-[2-2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide

The title compound (0.2 g, 80%) was prepared as a white solid from (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4mL) by an analogous procedure to that described in example 31. mp:107-109° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.13 (t, J=6.96 Hz, 3H), 2.81-2.93 (complex,1H), 3.03-3.19 (complex, 1H), 3.34-3.59 (complex, 4H), 3.69 (t, J=5.53Hz, 2H), 3.88 (dd, J=7.43 and 3.70 Hz, 1H), 4.15 (t, J=5.58 Hz, 2H),4.28 (t, J=4.24 Hz, 2H), 5.49 (bs, 1H, D₂O exchangeable), 6.43 (bs, 1H,D₂O exchangeable), 6.68-6.87 (complex, 6H), 7.15 (d, J=8.49 Hz, 2H).

EXAMPLE 34 (±)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide

The title compound (0.23 g, 74%) was prepared as a white solid from (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.8 mmol) obtained in example 26 and methylamine (40%solution) (2 mL) by an analogous procedure to that described in example32. mp: 97-99° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.14 (t, J=7.00 Hz, 3H), 2.76 (d, J=4.98 Hz,3H), 3.02-3.14 (complex, 1H), 3.35-3.45 (complex, 2H), 3.52 (t, J=4.57Hz, 2H), 3.68 (t, J=5.81 Hz, 2H), 4.14 (t, J=5.72 Hz, 2H), 4.22 (t,J=4.15 Hz, 2H), 4.80-4.90 (complex, 1H), 6.50 (bs, 1H), 6.55-6.89(complex, 6H), 7.11 (d, J=8.3 Hz, 2H), 7.88 (dd, J=7.06 and 3.74 Hz,1H).

EXAMPLE 35 (±)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide

The title compound (0.25 g, 67%) was prepared as a white solid from (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.8 mmol) obtained in example 26 and benzyl amine (0.095 g,0.88 mmol) by a procedure analogous to that described in example 32. mp:94-96° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.11 (t, J=7.00 Hz, 3H), 2.82-3.18 (complex,2H), 3.40-3.55 (complex, 4H), 3.70 (t, J=5.49 Hz, 2H), 3.94-3.98(complex, 1H), 4.14 (t, J=5.72 Hz, 2H), 4.23 (t, J=4.24 Hz, 2H),4.28-4.52 (complex, 2H), 6.60-6.87 (complex, 6H), 7.06-7.32 (complex,7H), CONH proton is too broad to observe.

EXAMPLE 36 (±)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide

The title compound (0.22 g, 74%) was prepared as a white solid from (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.25 g, 0.65 mmol) obtained in example 29 and benzylamine (0.076g, 0.71 mmol) by an analogous procedure to that described in example 32.mp: 92-93° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=7.00 Hz, 3H), 2.88-3.20 (complex,4H), 3.42-3.60 (complex, 2H), 3.73-3.87 (complex, 4H), 3.98-4.06(complex, 1H), 4.18 (t, J=5.72 Hz, 2H), 4.30-4.56 (complex, 2H),6.61-6.90 (complex, 4H), 7.00-7.43 (complex, 9H), CONH proton is toobroad to observe.

EXAMPLE 37 (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid

The title compound (0.3 g, 62%) was prepared as a gummy liquid from (±)methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.5 g, 1.2 mmol) obtained in example 7 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.24 (complex, 6H), 2.98, 3.04 (1H each, 2d.J=14.1 Hz each), 3.51 (t, J=4.25 Hz, 2H), 3.49-3.71 (complex, 4H), 4.15(t, J=5.63 Hz, 2H), 4.22 (t, J=4.48 Hz, 2H), 6.60-6.87 (complex, 6H),7.07 (d, J=8.67 Hz, 2H), COOH proton is too broad to observe.

EXAMPLE 38 (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, sodium salt

The title compound (0.12 g, 51%) was prepared as a white solid from (±)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-1-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.22 g, 0.57 mmol) obtained in example 37 by an analogousprocedure to that described in example 27.

¹H NMR (DMSO-d₆, 200 MHz): δ 0.96-1.08 (complex, 6H), 2.79 (s, 2H),3.28-3.52 (complex, 4H), 3.64 (t, J=5.30 Hz, 2H), 4.05-4.19 (complex,4H), 6.48-6.59 (complex, 1H), 6.62-6.86 (complex, 4H), 7.03-7.28(complex, 3H).

EXAMPLE 39 (±)2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid

The title compound (0.25 g, 42%) was prepared as a gummy liquid from (±)methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.6 g, 1.2 mmol) obtained in example 8 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.12 (t, J=6.82 Hz, 3H), 1.65 (bs, 1H, D₂Oexchangeable), 3.11-3.42 (complex, 4H), 3.50 (t, J=4.34 Hz, 2H), 3.68(t, J=5.67 Hz, 2H), 3.70-3.89 (complex, 2H), 4.14 (t, J=5.67 Hz, 2H),4.21 (t, J=4.15 Hz, 2H), 6.62-6.86 (complex, 6H), 7.03-7.12 (complex,4H), 7.18-7.30 (complex, 2H).

EXAMPLE 40 (±)2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt

The title compound (0.11 g, 48%) was prepared as a white solid from (±)2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.22 g, 0.45 mmol) obtained in example 39 by ananalogous procedure to that described in example 27.

¹H NMR (CDCl₃, 200 MHz): δ 1.02 (t, J=6.65 Hz, 3H), 2.75-2.92 (complex,4H), 3.39-3.58 (complex, 4H), 3.62 (bs, 2H), 4.04-4.20 (complex, 4H),6.49-6.82 (complex, 5H), 6.90-7.28 (complex, 6H), 7.49-7.13 (complex,1H).

EXAMPLE 41 (±)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid

The title compound (0.75 g, 77%) was prepared as a white solid from (±)methyl3-[4-[2-3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(1.0 g, 2.5 mmol) obtained in example 10 by a procedure analogous tothat described in example 26. mp: 90-93° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.18 (t, J=6.96 Hz, 3H), 2.88-3.13 (complex,2H), 3.41-3.63 (complex, 2H), 4.06 (dd, J=7.43 and 4.33 Hz, 1H),4.25-4.52 (complex, 4H), 4.61 (s, 2H), 6.80 (d, J=8.62 Hz, 2H),7.00-7.34 (complex, 6H), COOH proton is too broad to observe.

EXAMPLE 42 (±)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt

The title compound (0.12 g, 56%) was prepared as a white solid from (O)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.2 g, 0.51 mmol) obtained in example 41 by an analogous procedureto that described in example 27.

¹H NMR (CDCl₃, 200 MHz): δ 0.99 (t, J=6.97 Hz, 3H), 2.61-2.80 (complex,2H), 3.32-3.57 (complex, 1H), 3.60-3.72 (complex, 1H), 3.65-3.70(complex, 1H), 4.18 (bs, 2H), 4.30 (bs, 2H), 4.68 (s, 2H), 6.78 (d,J=8.4 Hz, 2H), 7.03-7.14 (complex, 5H), 7.42 (d, J=7.06 Hz, 1H).

EXAMPLE 43 (±)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid

The title compound (0.8 g, 69%) was prepared as a white solid from (±)methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate(1.2 g, 2.66 mmol) obtained in example 12 by an analogous procedure tothat described in example 26. mp: 102-104° C.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=7.01 Hz, 3H), 3.06 (t, J=4.98 Hz,2H), 3.08-3.63 (complex, 4H), 3.77-3.83 (complex, 4H), 4.15 (dd, J=4.15and 4.18 Hz, 1H), 4.28 (t, J=5.95 Hz, 2H), 6.59-6.79 (complex, 2H),6.96-7.36 (complex, 5H), 7.61-7.79 (complex, 3H), COOH proton is toobroad to observe.

EXAMPLE 44 (±)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid, sodium salt

The title compound (0.16 g, 76%) was prepared as a white solid from (±)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid (0.2 g, 0.457 mmol) obtained in example 43 by an analogousprocedure to that described in example 27. mp: 138-140° C.

¹H NMR (DMSO-d₆, 200 MHz): δ 0.98 (t, J=7.06 Hz, 3H), 2.72-2.90(complex, 1H), 2.92-3.21 (complex, 3H), 3.32-3.54 (complex, 2H),3.61-3.91 (complex, 5H), 4.28 (bs, 2H), 6.56 (t, J=7.00 Hz, 1H),6.73-7.00 (complex, 3H), 7.05-7.30 (complex, 2H), 7.38 (d, J=8.30 Hz,1H), 7.60-7.82 (complex, 3H).

EXAMPLE 45 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid

The title compound (0.06 g, 43%) was prepared as a brown syrupy liquidfrom (±) ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate(0.15 g, 0.40 mmol) obtained in example 13 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ2.85-3.19 (complex, 2H), 3.43 (t, J=4.15 Hz,2H), 3.61 (t, J=5.49 Hz, 2H), 4.07 (t, J=5.40 Hz, 2H), 4.16 (t, J=4.48Hz, 2H), 4.45 (bs, 1H), 6.50-6.82 (complex, 6H), 7.08 (d, J=7.88 Hz,2H), COOH and OH protons are too broad to observe.

EXAMPLE 46 (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid

The title compound (0.7 g, 46%) was prepared as a white solid from (±)ethyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate(1.7 g, 4.39 mmol) obtained in example 14 by a procedure analogous tothat described in example 26. mp: 74-76° C.

¹H NMR (CDCl₃, 200 z): δ 2.88-3.18 (complex, 4H), 3.69-3.79 (complex,4H), 4.15 (t, J=5.72 Hz, 2H), 4.45 (dd, J=6.73 and 4.79 Hz, 1H),4.51-4.97 (bs, D₂O exchangeable, 1H), 6.65-6.89 (complex, 4H), 6.94-7.17(complex, 4H), COOH proton is too broad to observe.

EXAMPLE 47 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid

The title compound (0.15 g, 67%) was prepared as a thick liquid from (±)ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate(0.24 g, 0.52 mmol) obtained in example 15 by a procedure analogous tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.40-2.80 (br, 1H, D₂O exchangeable),2.99-3.18 (complex, 2H), 3.51 (t, J=4.34 Hz, 2H), 3.70 (t, J=5.82 Hz,2H), 4.13-4.24 (complex, 5H), 4.51 (d, J=17.0 Hz, 2H), 6.60-6.89(complex, 6H), 7.10-7.37 (complex, 7H).

EXAMPLE 48 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid, sodium salt

The title compound (0.1 g, 73%) was prepared as a cream coloredhygroscopic solid from (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoic acid (0.13 g, 0.30 mmol) obtained in example 47 by a procedureanalogous to that described in example 27.

¹H NMR (DMSO-d₆, 200 MHz): δ 2.62-2.74 (complex, 1H), 2.89-2.98(complex, 1H), 3.48 (t, J=4.20 Hz, 2H), 3.67 (t, J=5.48 Hz, 2H),4.12-4.26 (complex, 5H), 4.65 (d, J=12.45 Hz, 2H), 6.45-6.84 (complex,6H), 7.12-7.25 (complex, 7H).

EXAMPLE 49 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid

The title compound (0.25 g, 67%) was prepared as a syrupy liquid from(±) ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate(0.4 g, 0.93 mmol), obtained in example 16 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 0.87 (t, J=7.15 Hz, 3H), 1.25-1.40 (complex,2H), 1.49-1.66 (complex, 2H), 2.95-3.15 (complex, 2H), 3.43-3.53(complex, 4H), δ 3.68 (t, J=5.49 Hz, 2H), 4.00-4.12 (complex, 1H), 4.14(t, J=5.65 Hz, 2H), 4.22 (t, J=4.25 Hz, 2H), 6.60-6.89 (complex, 6H),7.12 (d, J=8.39 Hz, 2H), COOH proton is too broad to observe.

EXAMPLE 50 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid, sodium salt

The title compound (0.12 g, 57%) was prepared as a hygroscopic creamcolor solid from (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid (0.2 g, 0.5 mmol) obtained in example 49 by an analogous procedureto that described in example 27.

¹H N (DMSO-d₆, 200 MHz): δ 0.78 (t, J=7.06 Hz, 3H), 1.16-1.56 (complex,4H), 2.52-2.64 (complex, 1H), 2.79-2.87 (complex, 1H), 2.99-3.18(complex, 2H), 3.40 (bs, 2H), 3.66 (t, J=5.31 Hz, 2H), 4.10-4.25(complex, 5H), 6.52-6.90 (complex, 6H), 7.12 (d, J=8.30 Hz, 2H).

EXAMPLE 51 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid

The title compound (0.17 g, 60%) was prepared as a greenish liquid from(±) ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate(0.3 g, 0.65 mmol) obtained in example 17 by a procedure analogous tothat described in example 26.

¹HMR (CDCl₃, 200 MHz): δ 0.86 (t, J=5.72 Hz, 3H), 1.25-1.33 (complex,4H), 1.41-1.75 (complex, 4H), 2.94-3.06 (complex, 2H), 3.36-3.58(complex, 4H), 3.68 (t, J=5.49 Hz, 2H), 4.01-4.06 (complex, 1H), 4.14(t, J=5.70 Hz, 2H), 4.22 (t, J=4.15 Hz, 2H), 6.71-7.08 (complex, 6H),7.12 (d, J=8.40 Hz, 2H), COOH proton is too broad to observe.

EXAMPLE 52 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid, sodium salt

The title compound (0.1 g, 52%) was prepared as a white hygroscopicsolid from (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid (0.18 g, 0.42 mmol) obtained in example 51 by an analogousprocedure to that described in example 27.

¹H NMR (DMSO-d₆, 200 MHz): δ 0.82 (t, J=5.72 Hz, 3H), 1.10-1.45(complex, 8H), 2.75-2.96 (complex, 2H), 3.35-3.56 (complex, 4H), 3.67(t, J=5.30 Hz, 2H), 4.08-4.21 (complex, 5H), 6.50-6.82 (complex, 6H),7.12 (d, J=8.00 Hz, 2H).

EXAMPLE 53 (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid

The title compound (0.1 g, 53%) was prepared as a colorless liquid from(±) methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.2 g, 0.461 mmol) obtained in example 19 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 2.40-2.80 (bs, 1H, D₂O exchangeable), 3.22(d, J=5.80 Hz, 2H), 3.49 (t, J=4.25 Hz, 2H), 3.67 (t, J=5.81 Hz, 2H),4.14 (t, J=5.81 Hz, 2H), 4.21 (t, J=4.16 Hz, 2H), 4.82 (t, J=590 Hz,1H), 6.61-7.02 (complex, 8H), 7.17-7.30 (complex, 5H).

EXAMPLE 54 (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid

The title compound (0.2 g, 51%) was prepared as a gummy solid from (±)methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.4 g, 0.9 mmol) obtained in example 21 by a procedure analogous tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 3.02 (t, J=5.00 Hz, 2H), 3.22 (d, J=6.25 Hz,2H), 3.68-3.78 (complex, 4H), 4.14 (t, J=5.81 Hz, 2H), 4.50 (t, J=6.19Hz, 1H), 4.90-5.40 (b, 1H, D₂O exchangeable), 6.58-6.86 (complex, 7H),6.94-7.07 (complex, 2H), 7.18-7.29 (complex, 4H).

EXAMPLE 55 (±)3-[4-[2-2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid, sodium salt

The title compound (0.05 g, 48%) was prepared as a hygroscopic solidfrom (±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid 0.1 g, 0.24 mmol) obtained in example 53 by a procedure analogousto that described in example 27.

¹H NMR (DMSO-d₆, 200 MHz) δ 2.81-3.09 (complex, 2H), 3.42 (bs, 2H), 3.65(t, J=4.5 Hz, 2H), 4.12 (bs, 4H), 4.22-4.32 (complex, 1H), 6.50-6.92(complex, 8H), 7.10-7.33 (complex, 5H).

EXAMPLE 56 (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate

The title compound (0.27 g, 87%) was prepared as a syrupy liquid from(±) methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.3 g, 0.69 mmol) obtained in example 19 by an analogous procedure tothat described in example 7.

¹H NMR (CDCl₃, 200 MHz): δ 1.39 (s, 3H), 3.09, 3.26 (1H each, 2d, J=13.7Hz each), 3.51 (t, J=4.30 Hz, 2H), 3.66-3.73 (complex, 5H), 4.15 (t,J=5.50 Hz, 2H), 4.22 (t, J=4.24 Hz, 2H), 6.61-7.01 (complex, 9H),7.12-7.22 (complex, 4H).

EXAMPLE 57 (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid

The title compound (0.13 g, 50%) was prepared as a pale yellowhygroscopic solid from (±) methyl2-methyl-3-[4-[2-2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.27 g, 0.60 mmol) obtained in example 56 by a procedure analogous tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.42 (s, 3H), 3.12, 3.29 (1H each, 2d, J=14.1Hz each), 3.50 (t, J=4.50 Hz, 2H), 3.69 (t, J=5.60 Hz, 2H), 4.16 (t,J=5.81 Hz, 2H), 4.22 (t, J=4.50 Hz, 2H), 6.62-7.17 (complex, 9H),7.21-7.30 (complex, 4H), COOH proton is too broad to observe.

EXAMPLE 58 (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid, sodium salt

The title compound (0.055 g, 46%) was prepared as a hygroscopic paleyellow powder from (±)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid (0.13 g, 0.28 mmol) obtained in example 57 by a procedure analogousto that described in example 27.

¹H NMR (CDCl₃, 200 MHz): δ 1.15 (s, 3H), 2.99-3.21 (complex, 2H), 3.47(bs, 2H), 3.67 (bs, 2H), 4.14 (bs, 4H), 6.53-6.90 (complex, 9H),7.08-7.30 (complex, 4H).

EXAMPLE 59 (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate

The title compound (0.96 g, 93%) was prepared as a pale yellow liquidfrom (±) methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(1.0 g, 2.22 mmol) obtained in example 21 by an analogous procedure tothat described in example 7.

¹H NMR (CDCl₃, 200 MHz): δ 1.40 (s, 3H), 3.03 (t, J=4.90 Hz, 2H), 3.09,3.27 (1H each, 2d, J=13.7 Hz each), 3.70-3.85 (complex, 7H), 4.16 (t,J=5.8.1 Hz, 2H), 6.60-6.89 (complex, 6H), 6.96-7.30 (complex, 7H).

EXAMPLE 60 (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid

The title compound (0.6 g, 65%) was prepared as a syrupy liquid from (±)methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.96 g, 2.00 mmol) obtained in example 59 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.42 (s, 3H), 3.03 (t, J=5.00 Hz, 2H), 3.12,3.30 (1H each, 2d, J=13.8 Hz each), 3.70-3.80 (complex, 4H), 4.15 (t,J=5.50 Hz, 2H), 6.58-7.08 (complex, 8H), 7.18-7.30 (complex, 5H), COOHproton is too broad to observe.

EXAMPLE 61 (±) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

The title compound (0.15 g, 38%) was prepared as a yellow liquid from(±)3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.77 mmol) obtained in example 29 and 4-nitrophenol by ananalogous procedure to that described in example 32.

¹H NMR (CDCl₃, 200 MHz): δ 1.24 (t, J=6.92 Hz, 3H), 3.04 (t, J=5.16 Hz,2H), 3.12 (d, J=6.63 Hz, 2H), 3.46-3.65 (complex, 1H), 3.70-3.86(complex, 5H), 4.16 (t, J=5.23 Hz, 2H), 4.26 (t, J=5.50 Hz, 1H),6.62-6.74 (complex, 2H), 6.84 (d, J=8.62 Hz, 2H), 6.94-7.22 (complex,6H), 8.23 (d, J=9.00 Hz, 2H).

EXAMPLE 62 (±)3-[4-(4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic acid

The title compound (0.4 g, 57%) was prepared as a syrupy liquid from (±)methyl3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate(0.8 g, 2.16 mmol) obtained in example 25 by an analogous procedure tothat described in example 26.

¹H NMR (CDCl₃, 200 MHz): δ 1.17 (t, J=7.00 Hz, 3H), 2.99-3.13 (complex,2H), 3.31-3.65 (complex, 4H), 4.01-4.24 (complex, 3H), 4.45 (d, J=3.40Hz, 2H), 4.52-4.59 (complex, 1H), 6.62-6.68 (complex, 6H), 7.14 (d,J=8.60 Hz, 2H), 7.27 (s, 5H), COOH proton is too broad to observe.

EXAMPLE 63 (±)3-[4-(4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic acid, sodium salt

The title compound (0.15 g, 75%) was prepared as a colorless hygroscopicsolid from (±)3-[4(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic acid (0.2 g, 0.44 mmol) obtained in example 62 by an analogousprocedure to that described in example 27.

¹H NMR (DMSO-d₆, 200 MHz): δ 0.99 (t, J=6.97 Hz, 3H), 2.60-2.90(complex, 2H), 3.30-3.65 (complex, 5H), 4.16 (d, J=5.00 Hz, 2H),4.40-4.65 (complex, 3H), 6.55-6.89 (complex, 6H), 7.14 (d, J=8.50 Hz,2H), 7.32 (s, 5H).

EXAMPLE 64 (±) 4-Nitrophenyl3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate

The title compound (0.6 g, 100%) was prepared as a dark brown liquidfrom (±)3-[4-(4-benzyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic acid (0.5 g, 1.34 mmol) obtained in example 62 and 4-nitrophenol by a procedure analogous to that described in example 32.

¹H NMR (CDCl₃, 200 MHz): δ 1.25 (t, J=7.00 Hz, 3H), 3.14 (d, J=6.60 Hz,2H), 3.33-3.55 (complex, 3H), 3.69-3.77 (complex, 1H), 4.05-4.31(complex, 3H), 4.46 (d, J=3.40 Hz, 2H), 4.55-4.61 (complex, 1H),6.63-6.68 (complex, 6H), 7.11-7.28 (complex, 7H), 7.52 (d, J=7.60 Hz,2H), 8.23 (d, J=9.00 Hz, 2H).

EXAMPLE 65 (−) Ethyl2-ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]propanoate

To a stirred solution of (−) ethyl2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 g, 2.1 mmol) in dryN,N-dimethyl formamide (0.8 mL) was added anhydrous potassium carbonate(1.16 g, 8.4 mmol) and stirred at about 25° C. for 20 minutes andmesylate of 2,3-dihydro-1,4-benzothiazin-1-ethanol (0.57 g, 2.1 mmol) in4 mL of dry DMF was added. The reaction mixture was stirred at ˜60° C.for 18 h, cooled to about 25° C. and filtered. The filtrate was dilutedwith ethylacetate (100 mL) and washed with water (3×100 mL), dried overanhydrous Na₂SO₄ and concentrated. The crude compound waschromatographed over silica gel using 10% ethylacetate in pet. ether aseluent to afford the title compound as pale brown colour oil (0.63 g,70%). [α]²⁵ _(D)=−12.5° (c=1.0, CHCl₃).

¹HNMR (CDCl₃): δ 1.10-1.30 (m, 6H), 2.94 (d, J=6.42 Hz, 2H), 3.01-3.10(m, 2H), 3.28-3.68 (m, 2H), 3.70-3.80 (m, 4H), 3.95 (t, J=6.42 Hz, 1H),4.10-4.22 (m, 4H), 6.55-6.74 (m, 2H), 6.80 (d, J=8.63 Hz, 2H), 6.98-7.10(m, 2H), 7.14 (d, J=8.63 Hz, 2H).

EXAMPLE 66 (±) Ethyl2-ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]propanoate

The title compound (0.9 g, 76%) was prepared as pale brown oil from (+)ethyl 2-ethoxy-3-4-hydroxyphenyl)propanoate (0.68 g, 2.8 mmol), mesylateof 2,3-dihydro-1,4-benzothiazin-1-ethanol (0.78 g, 2.8 mmol) andanhydrous K₂CO₃ (1.57 g, 11.3 mmol) by a similar procedure to thatdescribed in example 65. [α]²⁵ _(D)=10.8° (c=1.05. CHCl₃).

¹HNMR (CDCl₃): δ 1.10-1.30 (m, 6H), 2.93 (d, J=6.55 Hz, 2H), 3.00-3.07(m, 2H), 3.25-3.68 (m, 2H), 3.69-3.80 (m, 4H), 3.96 (t, J=6.55 Hz, 1H),4.10-4.20 (m, 4H), 6.55-6.75 (m, 2H), 6.80 (d, J=8.30 Hz, 2H), 6.98-7.10(m, 2H), 7.14 (d, J=8.30 Hz, 2H).

EXAMPLE 67 (−)2-Ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]propanoicacid

To a stirred methanolic solution of (−)-ethyl2-ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]propanoate(0.050 g, 0.12 mmol) obtained in example 65, aqueous sodium hydroxidesolution (0.050 g in 1 mL of water) was added at about 26° C. forhydrolysis of ester. After 20 minutes methanol was evaporated underreduced pressure below 30° C. (water bath temperature) immediately theresidue was diluted with ice cold water (5 mL) and cooled to ˜3° C. (icebath). The contents were acidified with 0.5 N HCl to the pH 7.0 andwashed thoroughly with 0.3% ethyl acetate in diethylether (3×10 mL),extracted with ethylacetate (3×10 mL). The extracts were washed withwater, brine, dried over anhydrous Na₂SO₄ and the solvent was evaporatedunder reduced pressure below 30° C. to yield the title compound as acolourless sticky mass (0.037 g, 80%). [α]²⁵ _(D)=−15.8° (c=1.050,MeOH).

¹HNMR (CDCl₃): δ 1.17 (t, J=7.01 Hz, 3H), 2.88-3.15 (m, 4H), 3.32-3.68(m, 2H), 3.70-3.80 (m, 4H), 4.00-4.10 (m, 1H), 4.15 (t, J=5.81 Hz, 2H),6.53-6.78 (m, 2H), 6.81 (d, J=8.63 Hz, 2H), 6.95-7.10 (m, 2H), 7.15 (d,J=8.63 Hz, 2H).

EXAMPLE 68 (±)2-ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]propanoicacid

The title compound (0.07 g, 78%) was prepared as off white sticky massfrom (+) ethyl2-ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]propanoate (0.1 g, 0.24 mmol) obtained in example 66 and sodiumhydroxide (0.1 g, 2.4 mmol) by a similar procedure to that described inexample 67.

¹HNMR (CDCl₃): δ 1.15 (t, J=6.98 Hz, 3H), 2.87-3.14 (m, 4H), 3.30-3.70(m, 2H) 3.72-3.82 (m, 4H), 4.00-4.12 (m, 1H), 4.12 (t, J=5.78 Hz, 2H),6.55-6.70 (m, 2H), 6.81 (d, J=8.62 Hz, 2H), 6.87-7.10 (m, 2H), 7.14 (d,J=8.62 Hz, 2H).

EXAMPLE 69 (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, magnesium salt

To a solution of (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (100 mg, 0.258 mmol) obtained in example 29 in methanol (5 mL) wasadded magnesium hydroxide (7.5 mg, 0.129 mmol) and stirred the reactionmixture at 30° C. for 24 hours and evaporated the solvent, washed theresidue with dry diethyl ether to remove unreacted starting material.The white powder was dried at 50° C. under vacuum for 7 hours to yieldthe title compound as a white powder (90 mg, 88%). mp: 158° C.-160° C.

¹H NMR (d₄ MeOH): δ 1.09 (t, J=7.00 Hz, 3H), 2.78 (dd, J=8.40 and 14.0Hz, 1H), 2.90-3.05 (m, 3H), 3.15-3.67 (m, 2H), 3.69-3.73 (m, 4H),3.75-3.90 (m, 1H), 4.14 (t, J=5.40 Hz, 2H), 6.55 (d, J=7.50 Hz, 1H),6.70-6.82 (m, 3H), 6.90 (d, J=7.50 Hz, 2H), 7.16 (d, J=8.40 Hz, 2H).

EXAMPLE 70 (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt

A mixture of (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.2 g, 0.51 mmol) obtained in example 67 and sodium methoxide(0.0279 g, 0.51 mmol) in methanol (4 mL) was stirred at room temperaturefor 2 hours. Methanol was removed under reduced pressure and residue wastriturated with ether (3×10 mL), separated solid was filtered and driedover P₂O₅ under vacuum to yield the title compound as an hygroscopicsolid (0.105 g, 50%).

¹HNMR (DMSO-d₆): δ 0.92-0.99 (t, J=6.64 Hz, 3H), 2.50-2.77 (m, 3H),3.02-3.10 (m, 3H), 3.44-3.50 (t, J=8.90 Hz, 1H), 3.55-3.69 (m, 4H),4.11-4.13 (m, 2H), 6.53-6.57 (d, J=7.05 Hz, 1H), 6.77-6.82 (d, J=8.30Hz, 2H), 6.90-7.12 (m, 3H), 7.20-7.22 (d, J=4.75 Hz, 2H).

EXAMPLE 71 (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, magnesium salt

A mixture of (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.320 g, 0.82 mmol) obtained in example 67 and magnesium hydroxide(0.024 g, 0.41 mmol) in methanol (12 mL) was refluxed for 15 h thencooled to room temperature, methanol was removed under reduced pressureseparated solid was triturated with pet ether and filtered and driedover P₂O₅ to yield the title compound (0.250 g, 73%). mp: 275° C.-285°C. [α]²⁵ D=−70.5° (c=1.0, CHCl₃).

¹HNMR (CDCl₃+CD₃OD): δ 1.10 (t, J=7.06 Hz, 3H), 2.81-3.02 (m, 3H),3.27-3.31 (m, 2H), 3.55-3.79 (m, 5H), 3.81-3.86 (t, J=3.74 Hz, 1H),4.12-4.17 (t, J=5.49 Hz, 2H), 6.00-6.54 (d, J=7.47 Hz, 1H), 6.79-6.82(d, J=7.56 Hz, 2H), 6.90-6.94 (m, 3H), 7.14-7.19 (d, J=8.39 Hz, 2H).

EXAMPLE 72 (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, arginine salt

L-Arginine (0.072 g, 0.4 mmol) in water (0.360 mL) was added to asolution of (−)3-[4-[2-2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.180 g, 0.46 mmol) obtained in example 67 in ethanol (4 mL) at50° C., then cooled to room temperature and stirred for 10 h. Solventwas removed under reduced pressure and traces of water was removedazeotropically by using toluene, separated solid was dried under vacuumto yield the title compound (0.175 g, 99.5%). mp 115° C.-125° C.[α]25_(D)=−13.00° (c=1.0, MeOH).

¹HNMR (CD₃OD): δ 1.05-1.12 (t, J=6.96 Hz, 3H), 1.69-1.85 (m, 4H),2.79-3.02 (m, 5H), 3.15-3.30 (m, 6H), 3.51-3.60 (q, J=6.73 Hz, 2H),3.62-3.81 (m, 6H), 4.12-4.18 (t, J=5.49 Hz, 2H), 6.54-6.58 (t, J=7.38Hz, 1H), 6.78-6.96 (m, 5H), 7.15-7.19 (d, J=8.21 Hz, 2H).

EXAMPLE 733-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, arginine salt

L-Arginine (0.152 g, 0.87 mmol) in water (0.7 mL) was added to asolution of3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.360 g, 0.97 mmol) obtained in example 26 in ethanol (9 mL) at50° C., then cooled to room temperature and stirred for 10 h. Solventwas removed under reduced pressure and traces of water was removedazeotropically by using toluene, separated solid was dried under vacuumto yield the title compound (0.3 g, 56%). mp: 180° C.-190° C.

¹HNMR (CD₃OD): δ 0.99-1.12 (t, J=6.92 Hz, 3H), 1.60-1.76 (m, 4H), 2.75(dd, J=10.0 Hz and 5.4 Hz, 2H), 3.05-3.39 (m, 8H), 3.45-3.74 (m, 10H),4.05 (t, J=5.40 Hz, 3H), 6.43-6.65 (m, 4H), 6.69 (d, J=8.62 Hz, 2H),7.06 (d, J=8.62 Hz, 2H).

EXAMPLE 74 (−) Ethyl2-ethoxy-3-[4-[2-2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]propanoate

Dry N,N-dimethyl formamide (800 mL) was added to a mixture of2,3-dihydro-1,4-benzoxazin-1-ethanol methanesulfonate (27.0 g, 0.1.5mmol), potassium carbonate (58.0 g, 0.420 mmol) and (−) ethyl2-ethoxy-3-(4-hydroxyphenyl)propanoate (25.0 g, 0.105 mmol) at 25° C.and the contents were heated at 60° C. for 16 h. After the completion ofthe reaction, the contents were filtered, washed with DMF, diluted withexcess water and extracted with ethylacetate. The organic layer waswashed thoroughly with water, brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound waschromatographed over silica gel using 5% ethylacetate in pet. ether aseluent to afford the title compound as a brown color liquid (18.2 g,44%).[α]²⁵ _(D)=−12.1° (c=1.0, CHCl₃).

¹HNMR (CDCl₃): δ 1.10-1.30 (m, 6H), 2.95 (d, J=6.74 Hz, 2H), 3.20-3.60(m, 4H), 3.66 (t, J=5.58 Hz, 2H), 3.96 (t, J=6.74 Hz, 1H), 4.10-4.30 (m,6H), 6.82 (d, J=8.63 Hz, 2H), 6.58-6.90 (m, 4H), 7.15 (d, J=8.63 Hz,2H).

EXAMPLE 75 (−)2-Ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]propanoicacid

To a solution of (−)-ethyl2-ethoxy-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]propanoate(17.0 g, 0.0426 mmol) obtained in example 74, in methanol (500 mL) 10%aqueous sodium hydroxide solution (135 mL) was added to at about 25° C.and stirred for 30 min. Methanol was evaporated under reduced pressureat 20° C. (water bath), the residue was diluted immediately with icecold water. The aqueous layer was washed with diethyl ether, acidifiedwith 2N HCl, and extracted with ethylacetate. The organic layer wasthoroughly washed with water, brine, dried over Na₂SO₄ and the solventwas evaporated under reduced pressure at 25° C. to yield the titlecompound as a pale brown thick liquid (14.1 g, 89%). %).[α]²⁵_(D)=−18.3° (c=1.0, MeOH).

¹HNMR (CDCl₃): δ 1.17 (t, J=6.97 Hz, 3H), 2.95 (dd, J=5.99 and 14.11 Hz,1H), 3.08 (dd, J=4.24 and 14.11 Hz, 1H), 3.30-3.65 (m, 4H), 3.69 (t,J=5.49 Hz, 2H), 4.00-4.10 (m, 1H), 4.12 (t, J=5.49 Hz, 2H), 4.20 (t,J=4.38 Hz, 2H), 6.80 (d, J=8.40 Hz, 2H), 6.55-6.90 (m, 4H), 7.1.5 (d,J=8.40 Hz, 2H).

EXAMPLE 76 (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, magnesium salt

Magnesium hydroxide (1.10 g, 0.0188 mmol) was added to a stirredsolution of (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (14.0 g, 0.0377 mmol) obtained in example 75, in dry methanol (12mL) under nitrogen atmosphere at 25 C and the contents were refluxed for18 h. The solvent was evaporated under reduced pressure and the solidwas thoroughly triturated with dry diethyl ether and dried under highvacuum at 65° C. (oil bath) for 30 minutes to yield the title compoundas a white solid (12.2 g, 83%). mp: 255° C.-260° C. [α]²⁵ _(D)=−22.3°(c=1.0, MeOH: CHCl₃ (1:1)).

¹HNMR (CDCl₃+CD₃OD): δ 0.99 (t, J=6.97 Hz, 3H), 2.70 (dd, J=8.40 and4.12 Hz, 1H), 2.90 (dd, J=4.12 and 14.20 Hz, 1H), 3.10-3.55 (m, 4H),3.57 (t, J=5.40 Hz, 2H), 3.70-3.80 (m, 1H), 4.00-4.10 (m, 4H), 6.70 (d,J=8.31 Hz, 2H), 6.35-6.80 (m, 4H), 7.07 (d, J=8.31 Hz, 2).

EXAMPLE 77 (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, arginine salt

L-Arginine (6.16 g, 0.0354 mmol) in water (20 mL) was added to a stirredsolution of (−)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (19.6 g, 0.0395 mmol) obtained in example 75 in ethanol (300 mL) at50° C., then cooled to room temperature and stirred for 15 h. Thesolvent was removed azeotropically using toluene, separated solid wastriturated with dry diethyl ether, filtered and dried under vacuum overCaCl₂ overnight to yield the title compound as a white color powder(16.2 g, 76%). mp: 184° C.-186° C. [α]²⁵ _(D)=−23.4° (c=1.0, MeOH).

¹HNMR (CD₃OD): δ 0.99 (t, J=7.06 Hz, 3H), 1.50-1.85 (m, 4H), 2.68 (dd,J=8.54 Hz and 14.22 Hz, 1H), 2.80 (dd, J=4.35 Hz and 14.22 Hz, 1H),3.00-3.20 (m, 3H), 3.25-3.48 (m, 4H), 3.56 (t, J=5.39 Hz, 2H), 3.70 (dd,J=4.24, 8.39 Hz, 1H), 4.06 (m, 4H), 6.66 (d, J=8.53 Hz, 2H), 6.75-6.35(m, 4H), 7.06 (d, J=8.53 Hz, 2H).

The compounds of the present invention lowered random blood sugar level,triglyceride, total cholesterol, LDL, VLDL and increased HDL. This wasdemonstrated by in vitro as well as in vivo animal experiments.

Demonstration of Efficacy of Compounds

A) In Vitro:

a) Determination of hPPARα Activity

Ligand binding domain of hPPARα was fused to DNA binding domain of Yeasttranscription factor GAL4 in eucaryotic expression vector. Usingsuperfect (Qiagen, Germany) as transfecting reagent HEK-293 cells weretransfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat different concentrations after 42 hrs of transfection and incubatedovernight. Luciferase activity as a function of compoundbinding/activation capacity of PPARα was measured using Packard Luclitekit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, PeterBroag and Melvyn Hollis. Gene, 1992, 118: 137-141; SuperfectTransfection Reagent Handbook. February 1997. Qiagen, Germany).

b) Determination of hPPARγ Activity

Ligand binding domain of hPPARγ1 was fused to DNA binding domain ofYeast transcription factor GAL4 in eucaryotic expression vector. Usinglipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cellswere transfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat 1 μM concentration after 48 hrs of transfection and incubatedovernight. Luciferase activity as a function of drug binding/activationcapacity of PPARγ1 was measured using Packard Luclite kit (Packard, USA)in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag andMelvyn Hollis. Gene. 1992, 118: 137-141; Guide to EukaryoticTransfections with Cationic Lipid Reagents. Life Technologies, GIBCOBRL, USA).

c) Determination of HMG CoA Reductase Inhibition Activity

Liver microsome bound reductase was prepared from 2% cholestyramine fedrats at mid-dark cycle. Spectrophotometric assays were carried out in100 mM KH₂PO₄, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg ofliver microsomal enzyme. Total reaction mixture volume was kept as 1 ml.Reaction was started by addition of HMG CoA. Reaction mixture wasincubated at 37° C. for 30 min and decrease in absorbance at 340 nm wasrecorded. Reaction mixture without substrate was used as blank(Goldstein, J. L and Brown, M. S. Progress in understanding the LDLreceptor and HMG CoA reductase, two membrane proteins that regulate theplasma cholesterol. J. Lipid Res. 1984, 25: 1450-1461). The testcompounds inhibited the HMG CoA reductase enzyme.

B) In Vivo

a) Efficacy in Genetic Models

Mutation in colonies of laboratory animals and different sensitivitiesto dietary regimens have made the development of animal models withnon-insulin dependent diabetes and hyperlipidemia associated withobesity and insulin resistance possible. Genetic models such as db/dband ob/ob (Diabetes, (1982) 31(1): 1-6) mice and zucker fa/fa rats havebeen developed by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab.(1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, U.S., are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwere tested for blood sugar and triglycerides lowering activities.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animalhouse, were used in the experiment. The mice were provided with standardfeed (National Institute of Nutrition (NIN), Hyderabad, India) andacidified water, ad libitum. The animals having more than 350 mg/dlblood sugar were used for testing. The number of animals in each groupwas 4.

Test compounds were suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 0.1 mg to 30 mg/kg through oralgavage daily for 6 days. The control group received vehicle (dose 10ml/kg). On 6th day the blood samples were collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglyceride levels were measuredspectrometrically, by glucose oxidase and glycerol-3-PO₄oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula.

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test.

Reduction in Blood Triglyceride Compound Dose (mg/kg) Glucose Level (%)Lowering (%) Example 41 3 53 27 Example 50 3 45 23 Example 44 10 47 74

The ob/ob mice were obtained at 5 weeks of age from Bomholtgard, Denmarkand were used at 8 weeks of age. Zucker fa/fa fatty rats were obtainedfrom IffaC redo, France at 10 weeks of age and were used at 13 weeks ofage. The animals were maintained under 12 hour light and dark cycle at25±1° C. Animals were given standard laboratory chow (NIN, Hyderabad,India) and water, ad libitum (Fujiwara, T., Yoshioka, S., Yoshioka, T.,Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabeticagent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats.Diabetes, 1988, 37: 1549-1558).

The test compounds were administered at 0.1 to 30 mg/kg/day dose for 9days. The control animals received the vehicle (0.25%carboxymethylcellulose, dose 10 ml/kg) through oral gavage.

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride, glucose, free fatty acid, total cholesterol and insulinestimations. Measurement of plasma triglyceride, glucose, totalcholesterol were done using commercial kits (Dr. Reddy's Laboratory,Diagnostic Division, India). The plasma free fatty acid was measuredusing a commercial kit from Boehringer Mannheim, Germany. The plasmainsulin was measured using a RIA kit (BARC, India). The reduction ofvarious parameters examined are calculated according to the formulagiven below.

In ob/ob mice oral glucose tolerance test was performed after 9 daystreatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg ofglucose orally. The blood samples were collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

The experimental results from the db/db mice, ob/ob mice, Zucker fa/farats suggest that the novel compounds of the present invention alsopossess therapeutic utility as a prophylactic or regular treatment fordiabetes, obesity, cardiovascular disorders such as hypertension,hyperlipidaemia and other diseases; as it is known from the literaturethat such diseases are interrelated to each other.

Blood glucose level and triglycerides are also lowered at doses greaterthan 10 mg/kg. Normally, the quantum of reduction is dose dependent andplateaus at certain dose.

b) Plasma Triglyceride and Cholesterol Lowering Activity inHypercholesterolemic Rat Models

Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.Animals were maintained under 12 hour light and dark cycle at 25±1° C.Rats of 180-200 gram oody weight range were used for the experiment.Animals were made hypercholesterolemic by feeding 2% cholesterol and 1%sodium cholate mixed with standard laboratory chow [National Instituteof Nutrition (NIN), Hyderabad, India] for 6 days. Throughout theexperimental period the animals were maintained on the same diet (Petit,D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate onliver lipids and lipoprotein synthesis in normo- and hyperlipidemicrats. Atherosclerosis. 1988, 74: 215-225).

The test compounds were administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 10 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment. The blood wascollected from the retro-orbital sinus through heparinised capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement ofplasma triglyceride, total cholesterol and HDL were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula.

Total Example Dose Triglyceride Cholesterol HDL LDL VLDL No. mg/kg (%) ↓(%) ↓ (%) ↑ (%) ↓ (%) ↓ Example 1 43 57 37 58 79 27 Example 1 50 42 4644 53 44 ↓ reduction; ↑ increase

C) Plasma Triglyceride and Total Cholesterol Lowering Activity in SwissAlbino Mice and Guinea Pigs

Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NINand housed in DRF animal house. All these animals were maintained under12 hour light and dark cycle at 25±1° C. Animals were given standardlaboratory chow (NIN, Hyderabad. India) and water, ad libitum. SAM of20-25 g body weight range and Guinea pigs of 500-700 g body weight rangewere used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V.,Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil andnicotinic acid on plasma lipoprotein levels in normal and hyperlipidemicmice. Atherosclerosis. 1988, 70: 107-114).

The test compounds were administered orally to Swiss albino mice at 0.3to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle(0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds wereadministered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6days. Control animals were treated with vehicle (0.25%Carboxymethylcellulose; dose 5 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergermeyer, H. O., Ed., 1963. 211-214; Trinder, P. Ann. Clin.Biochem. 1969, 6: 24-27). Measurement of plasma triglyceride, totalcholesterol and HDL were done using commercial kits (Dr. Reddy'sDiagnostic Division, Hyderabad, India).

Triglyceride Lowering Compound Dose (mg/kg) (%) Example 33 3 55 Example41 10 54 Example 43 3 49 Example 63 3 57

C) Body Weight Reducing Effect in Cholesterol Fed Hamsters:

Male Syrian Hamsters were procured from NW, Hyderabad, India. Animalswere housed at DRF animal house under 12 hour light and dark cycle at25±1° C. with free access to food and water. Animals were maintainedwith 1% cholesterol containing standard laboratory chow (NIN) from theday of treatment.

The test compounds were administered orally at 1 to 30 mg/kg/day dosefor 15 days. Control group animals were treated with vehicle (Mill Qwater, dose 10 ml/kg/day). Body weights were measured on every 3^(rd)day.

Dose Body weight Example No. (mg/kg/day) Reduction (%) Example 27 10 12Example 30 10 18Formulae for Calculation:1. Percent reduction in Blood sugar/triglycerides/total cholesterol werecalculated according to the formula:

${\text{Percent~~reduction}\mspace{14mu}(\%)} = {\left\lbrack {1 - \frac{{TT}/{OT}}{{TC}/{OC}}} \right\rbrack \times 100}$OC=Zero day control group valueOT=Zero day treated group valueTC=Test day control group valueTT=Test day treated group value2. LDL and VLDL cholesterol levels were calculated according to theformula:

${{LDL}\mspace{14mu}\text{cholesterol~~in~~mg/dl}} = \mspace{130mu}{\left\lbrack {\text{Total~~cholesterol} - {{HDL}\mspace{14mu}\text{cholesterol}} - \frac{\text{Triglyceride}}{5}} \right\rbrack\text{mg/dl}}$VLDL cholesterol in mg/dl=[Total cholesterol−HDL cholesterol−LDLcholesterol] mg/dl

1. A compound which is selected from the group consisting of (±)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid; (+)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid; (−)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid; (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (±)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (+)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (−)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (±)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid; (+) 3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoic acid; (−)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid; (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid; (+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid; (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid; (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid; (+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid;(−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid; (±)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid; (+)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid; (−)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid; and the pharmaceutically acceptable salts thereof.
 2. Acompound which is selected from the group consisting of (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (±) 3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid; (+)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (−)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid; (+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid; (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid; (±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid; (+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid; (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid; (±)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid; (+)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid; (−)2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoic acid; and the pharmaceutically acceptable salts thereof.
 3. Acompound which is selected from the group consisting of (±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid;(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (−)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (±)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (+)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; (−)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid; and the pharmaceutically acceptable salts thereof.
 4. The compoundaccording to claim 1, 2, or 3, wherein the pharmaceutically acceptablesalt is selected from: Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn,N,N′-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol,2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine,piperazine, piperidine, procaine, purines, theobromine, triethylamine,trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine,ethylenediamine, N,N′-diphenylethylenediamine,N,N′-dibenzylethylenediamine, N-benzyl phenylethylamine, choline,choline hydroxide, dicyclohexylamine, benzylamine, phenylethylamine,dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine,purine, spermidine, alkylphenylamine, glycinol, phenyl glycinol,glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine,cystine, cysteine, methionine, proline, hydroxy proline, histidine,ornithine, lysine, arginine, serine, threonine, phenylalanine,guanidine, substituted guanidine, ammonium, substituted ammonium oraluminum salts.
 5. The compound according to claim 4, wherein thepharmaceutically acceptable salt is Na or Mg.